Pyrimidine derivatives and anti-viral agent containing the same as active ingredient thereof

ABSTRACT

The disclosure concerns pyrimidine derivatives represented by the following general formulas [I] and [I′] and having antiviral activity, particularly antiretroviral activity such as anti-HIV activity:                    
     and pharmaceutical compositions having antiviral activity and comprising the above-described derivative(s) as an active ingredient.

This is a continuation of application Ser. No. 07/590,475 filed on Sep.28, 1990, now abandoned.

FIELD OF THE INVENTION

The present invention relates to novel 6-substituted acyclopyrimidinederivatives and antiviral agents containing the derivative as the activeingredients.

BACKGROUND OF THE INVENTION

Infectious diseases caused by human acquired immunodeficiency virus(HIV), which is a type of retrovirus, have recently become a serioussocial problem. A compound of 3′-deoxy-3′-azidothymidine is known as anucleoside compound used in the clinical treatment for diseases causedby HIV-infection. However, this compound has side-effects since it alsoexhibits considerable strong toxicity in the host cells.

Although some 2′,3′-dideoxyribonucleosides are known as nucleosidecompounds exhibiting an anti-viral activity, it is still necessary todevelop a substance possessing a higher activity and lower toxicity tothe host cell (Hiroaki Mitsuya, Bodily Defense, Vol. 4, pp.213-223(1987)).

On the other hand, various acyclonucleoside compounds have beensynthesized since Acyclovir (acycloguanosine) was developed as anantiviral substance effective against herpes virus (C. K. Chu and S. J.Culter, J. Heterocyclic Chem., 23, p.289 (1986)). However, noacyclonucleoside compound having a sufficient activity especiallyagainst retroviruses has yet been discovered.

We have focussed our attention on 6-substituted acyclopyrimidinenucleoside compounds and have synthesized various novel 6-substitutedacyclopyrimidine nucleoside derivatives and screened those compounds todetect effective antiviral agents, especially to the retrovirus, inorder to provide antiviral agents exhibiting an effective activityparticularly against retroviruses.

Some 6-substituted acyclopyrimidine nucleoside compounds such as6-fluoro substituted derivatives, 6-alkylamino substituted derivatives(DD-A-232492) and 6-methyl substituted derivatives (C. A. 107, 129717w(1987)) are known; however, the antiviral activity of these compoundshas not been described.

As a result of our researches for compounds exhibiting an effectiveantiviral activity, particularly anti-retroviral activity, we found thatspecific 6-substituted pyrimidine nucleoside compounds according to theinvention satisfy the above demand to achieve the present invention.

SUMMARY OF THE INVENTION

The present invention concerns 6-substituted acyclopyrimidine nucleosidederivatives represented by the following general formula I;

wherein R¹ represents a hydrogen atom, halogen atom, alkyl, cycloalkyl,alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, arylcarbonylalkyl,arylthio or aralkyl group;

R² represents an arylthio, alkylthio, cycloalkylthio, arylsulfinyl,alkylsulfinyl, cycloalkylsulfinyl, alkenyl, alkynyl, aralkyl,arylcarbonyl, arylcarbonylalkyl or aryloxy group, those groupsoptionally substituted by one or more of substituents selected from ahalogen atom, alkyl, halogenated alkyl, alkoxy, hydroxyl, nitro, amino,cyano and acyl groups;

R³ represents a hydrogen atom, methyl, branched alkyl or—CH₂—Z—(CH₂)_(n)—R⁵ group where R⁵ represents a hydrogen atom, halogenatom, hydroxyl, heterocyclic carbonyloxy, formyloxy, alkylcarbonyloxy,cycloalkylcarbonyloxy, aralkylcarbonyloxy, arylcarbonyloxy, azido,alkoxycarbonyloxy, N-alkylcarbamoyloxy, N-arylcarbamoyloxy, alkoxy,aralkyloxy, branched alkyl, cycloalkyl or aryl group, thealkoxycarbonyloxy to aryl groups mentioned above as R⁵ optionallysubstituted by one or more substituents selected from a halogen atom,aryl, alkyl, alkoxy and halogenated alkyl groups, Z represents anoxygen, sulfur atom or methylene group, and n represents 0 or an integerof 1 to 5,

R⁴ represents a hydrogen atom, alkyl or aralkyl group,

X and Y represent an oxygen or sulfur atom independently, provided thatwhen R⁴ and Z represent a hydrogen atom and oxygen atom respectively R⁵does not represent a hydroxyl group, or the following general formulaI′;

wherein R¹, R², R³ and Y have the same meanings as defined for theformula I above, pharmaceutically acceptable salts thereof and antiviralagents containing the derivative or the salt thereof as an activeingredient.

DETAILED DESCRIPTION OF THE INVENTION

The 6-substituted acyclopyrimidine nucleoside derivatives according tothe invention are represented by the general formula I or I′.

The group of R¹ represents a hydrogen atom; halogen atom such aschlorine, iodine, bromine and fluorine; alkyl group such as methyl,ethyl, n-propyl, i-propyl and n-butyl; cycloalkyl group such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;alkenyl group such as vinyl, propenyl, butenyl, phenylvinyl, bromovinyl,cyanovinyl, alkoxycarbonylvinyl and carbamoylvinyl; alkynyl group suchas ethynyl, propynyl and phenylethynyl; alkylcarbonyl group such asacetyl, propionyl, and i-butyryl; arylcarbonyl group such as benzoyl andnaphthoyl; arylcarbonylalkyl group such as phenacyl; arylthio group suchas phenylthio, tolylthio and naphthylthio; or aralkyl group such asbenzyl.

The group of R² represents an arylthio group such as phenylthio andnaphthylthio; alkylthio group such as methylthio, ethylthio, propylthio,butylthio and pentylthio; cycloalkylthio group such as cyclopentylthio,cyclohexylthio and cycloheptylthio; arylsulfinyl group such asphenylsulfinyl; alkylsulfinyl group such as methylsulfinyl,ethylsulfinyl and butylsulfinyl; cycloalkylsulfinyl group such ascyclopentylsulfinyl and cyclohexylsulfinyl; alkenyl group such as vinyl,propenyl and phenylvinyl; alkynyl group such as ethynyl, propynyl andphenylethynyl; aralkyl group such as benzyl; arylcarbonyl group such asbenzoyl; arylcarbonylalkyl group such as phenacyl; or aryloxy group suchas phenoxy, and those groups may be optionally substituted by one ormore of substituents selected from a halogen atom such as chlorine,bromine, fluorine and iodine, alkyl group such as methyl, ethyl, propyl,butyl and pentyl, a halogenated alkyl group such as trifluoromethyl,alkoxy group such as methoxy, ethoxy, propoxy and butoxy, hydroxylgroup, nitro group, amino group, cyano group and acyl group such asacetyl.

The group of R³ represents a hydrogen atom, methyl group, branched alkylgroup such as i-propyl and t-butyl or —CH₂—Z—(CH₂)_(n)—R⁵ group where R⁵represents a hydrogen atom; halogen atom such as fluorine, chlorine,iodine and bromine; hydroxyl group; heterocyclic carbonyloxy group suchas nicotinoyloxy; formyloxy group; optionally branched alkylcarbonyloxygroup such as acetoxy, propyonyloxy, n-butyryloxy, i-butyryloxy,valeryloxy, hexanoyloxy, heptanoyloxy and decanoyloxy;cycloalkylcarbonyloxy group such as cyclohexylcarbonyloxy;aralkylcarbonyloxy group such as benzylcarbonyloxy; arylcarbonyloxygroup such as benzoyloxy, toluoylcarbonyloxy and naphthoylcarbonyloxygroup; azido group; alkoxycarbonyloxy group such as methoxycarbonyloxy,ethoxycarbonyloxy, n-propoxycarbonyloxy, i-propoxycarbonyloxy,n-butoxycarbonyloxy and t-butoxycarbonyloxy group, optionallysubstituted by one or more substituents selected from a halogen atomsuch as fluorine, chlorine, bromine and iodine, aryl group such asphenyl, toluyl and naphthyl, alkyl group such as methyl, ethyl,n-propyl, i-propyl, n-butyl and t-butyl, alkoxy group such as methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy and halogenatedalkyl group such as trifluoromethyl; N-alkylcarbamoyloxy group such asN-methylcarbamoyloxy, N-ethylcarbamoyloxy, N-propylcarbamoyloxy,N-butylcarbamoyloxy and N-pentylcarbamoyloxy, optionally substituted byone or more substituents selected from a halogen atom such as fluorine,chlorine, bromine and iodine, aryl group such as phenyl, toluyl andnaphthyl, alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyland t-butyl, alkoxy group such as methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy and t-butoxy and halogenated alkyl group such astrifluoromethyl; N-arylcarbamoyloxy group such as N-phenylcarbamoyloxyand N-tolylcarbamoyloxy, optionally substituted by one or moresubstituents selected from a halogen atom such as fluorine, chlorine,bromine and iodine, aryl group such as phenyl, toluyl and naphthyl,alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl andt-butyl, alkoxy group such as methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy and t-butoxy and halogenated alkyl group such astrifluoromethyl; N-alkylthiocarbamoyloxy group such asN-methytiocarbamoyloxy, N-ethylthiocarbamoyloxy,N-propylthiocarbamoyloxy, N-butylthiocarbamoyloxy andN-pentylthiocarbamoyloxy, optionally substituted by one or moresubstituents selected from a halogen atom such as fluorine, chlorine,bromine and iodine, aryl group such as phenyl, toluyl and naphthyl,alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl andt-butyl, alkoxy group such as methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy and t-butoxy and halogenated alkyl group such astrifluoromethyl; N-arylthiocarbamoyloxy group such asN-phenylthiocarbamoyloxy and N-tolylthiocarbamoyloxy, optionallysubstituted by one or more substituents selected from a halogen atomsuch as fluorine, chlorine, bromine and iodine, aryl group such asphenyl, toluyl and naphthyl, alkyl group such as methyl, ethyl,n-propyl, i-propyl, n-butyl and t-butyl, alkoxy group such as methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy and halogenatedalkyl group such as trifluoromethyl; alkoxy group such as methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, n-pentyloxy andn-hexyloxy group, optionally substituted by one or more substituentsselected from a halogen atom such as fluorine, chlorine, bromine andiodine, aryl group such as phenyl, toluyl and naphthyl, alkyl group suchas methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, alkoxy groupsuch as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy andhalogenated alkyl group such as trifluoromethyl; branched alkyl groupsuch as i-propyl, i-butyl, sec-butyl, t-butyl, i-heptyl and i-hexyl,optionally substituted by one or more substituents selected from ahalogen atom such as fluorine, chlorine, bromine and iodine, aryl groupsuch as phenyl, toluyl and naphthyl, alkyl group such as methyl, ethyl,n-propyl, i-propyl, n-butyl and t-butyl, alkoxy group such as methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy and halogenatedalkyl group such as trifluoromethyl; cycloalkyl group such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,optionally substituted by one or more substituents selected from ahalogen atom such as fluorine, chlorine, bromine and iodine, aryl groupsuch as phenyl, toluyl and naphthyl, alkyl group such as methyl, ethyl,n-propyl, i-propyl, n-butyl and t-butyl, alkoxy group such as methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy and halogenatedalkyl group such as trifluoromethyl; or aryl group such as phenyl,optionally substituted by one or more substituents selected from ahalogen atom such as fluorine, chlorine, bromine and iodine, aryl groupsuch as phenyl, toluyl and naphthyl, alkyl group such as methyl, ethyl,n-propyl, i-propyl, n-butyl and t-butyl, an alkoxy group such asmethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy andhalogenated alkyl group such as trifluoromethyl, and Z represents anoxygen, sulfur atom or methylene group, and n represents 0 or an integerof 1 to 5,

R⁴ represents a hydrogen atom; optionally branched alkyl group such asmethyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl; or aralkyl groupsuch as benzyl.

X and Y represent oxygen or sulfur atom independently.

In the above formula I, when R⁴ and Z represent a hydrogen atom andoxygen atom respectively, R⁵ does not represent a hydroxyl group.

The preferred compounds according to the invention have R¹ of a hydrogenatom, halogen atom, C₁ to C₅ alkyl group or C₂ to C₅ alkenyl group,particularly C₁ to C₅ alkyl group; R² of C₆ to C₁₀ arylthio group, C₃ toC₁₀ cycloalkylthio group or C₇ to C₁₁ aralkyl group, particularly C₆ toC₁₀ arylthio, C₃ to C₁₀ cycloalkylthio or C₇ to C₁₁ aralkyl group,optionally substituted by one or more substituents selected from ahalogen atom, C₁ to C₅ alkyl, C₁ to C₅ alkoxy and nitro groups; R³ of ahydrogen atom, methyl or —CH₂—Z—(CH₂)_(n)—R⁵ group where R⁵ represents ahydrogen atom, halogen atom, hydroxyl, heterocyclic carbonyloxy, C₂ toC₁₁ alkylcarbonyloxy, C₄ to C₁₀ cycloalkylcarbonyloxy, C₈ to C₁₂aralkylcarbonyloxy, C₇ to C₁₃ arylcarbonyloxy, C₂ to C₁₁alkoxycarbonyloxy, C₈ to C₁₀ aralkyloxycarbonyloxy, C₂ to C₈N-alkylcarbamoyloxy, C₇ to C₁₃ arylcarbamoyloxy, C₂ to C₈alkylthiocarbamoyloxy, C₇ to C₁₃ arylthiocarbamoyloxy, C₁ to C₁₀ alkoxy,C₇ to C₁₃ aralkyloxy, azido, C₃ to C₅ branched alkyl, C₅ to C₇cycloalkyl or C₆ to C₁₀ aryl group optionally substituted by one or moresubstituents selected from a halogen atom, aryl, alkyl, alkoxy andhalogenated alkyl groups, Z represents an oxygen, sulfur atom ormethylene group, and n represents 0 or an integer of 1 to 5; R⁴ of ahydrogen atom, C₁ to C₁₃ alkyl or C₇ to C₁₁ aralkyl group; X of anoxygen or sulfur atom; and Y of an oxygen or sulfur atom; provided thatwhen R⁴ and Z represent a hydrogen atom and oxygen atom respectively R⁵does not represent hydroxyl group,

Examples of the preferred compounds according to the present inventionare listed in Table 1 below. t,120

TABLE 1

Com- Melting pound point No. R¹ R² R³ R⁴ X Y (° C.)  1 —CH₃

—H O S 112˜ 113  2 ″ ″ ″ ″ ″ O 112˜ 113  3 ″

″ ″ ″ ″ 155.5˜ 156.6  4 ″ ″ ″ ″ ″ S 144˜ 145  5 ″

″ ″ ″ O 132˜ 133  6 ″

″ ″ ″ ″ 100˜ 115  7 ″

″ ″ ″ 120˜ 121  8 ″ ″

″ ″ ″ 107˜ 108  9 ″ ″

″ ″ ″ 9˜102  10 —CH₃

—H O O 80˜81  11 ″ ″

″ ″ ″ 101˜ 102  12 ″ ″

″ ″ ″ 132˜ 133  13 ″ ″

″ ″ ″ 139˜ 140  14 ″ ″

″ ″ ″ 115˜ 119  15 ″

″ ″ ″ 95˜97  16 ″

″ ″ ″ 175˜ 176  17 ″ ″

″ ″ ″ 148˜ 150  18 ″ ″

″ ″ ″ 157˜ 159  19 ″

″ ″ ″ 107˜ 109  20 ″ ″

″ ″ ″ 102˜ 104  21 —CH₃

—H O O 74˜80  22 ″ ″

″ ″ ″ 148˜ 150  23 ″ ″

″ ″ ″ 133˜ 134  24 ″ ″

″ ″ ″ 91˜92  25 ″ ″

″ ″ ″ 136˜ 137  26 ″ ″

″ ″ ″ 123˜ 124  27 ″ ″

″ ″ ″ 238˜ 242  28 ″ ″

″ ″ ″ 229˜ 230  29 ″ ″

″ ″ ″ 158˜ 160  30 ″ ″

″ ″ ″ 124˜ 127  31 ″ ″

″ ″ ″ 157˜ 158  32 —CH₃

—H O O 159˜ 161  33 ″ ″

″ ″ Oil  34 ″ ″

—CH₃ ″ ″ 74˜75  35 ″ ″

—H ″ ″  36 ″ ″

″ ″ ″  37 ″ ″

″ ″ ″  38 ″ ″

″ ″ ″  39 ″ ″

″ ″ ″  40 ″ ″

″ ″ ″  41 ″ ″

″ ″ ″ 136˜ 138  42 ″ ″

″ ″ S  43 —CH₃

—CH₃ O S  44 ″ ″

—H ″ ″  45 ″ ″

″ ″ ″  46 ″ ″

″ ″ ″  47 ″ ″

″ ″ ″  48 ″ ″

″ ″ ″  49 ″ ″

″ ″ ″  50 ″ ″

″ ″ ″  51 ″ ″

″ ″ ″  52 ″ ″

″ ″ ″  53 ″ ″

″ ″ ″  54 —CH₃

—H O S  55 ″ ″

″ ″ ″  56 ″ ″

″ ″ ″  57 ″ ″

″ ″ ″  58 ″ ″

″ ″ ″  59 ″ ″

″ ″ ″  60 ″ ″

″ ″ ″  61 ″ ″

″ ″ ″  62 ″ ″

″ ″ ″  63 ″ ″

″ ″ ″  64 ″ ″

″ ″ ″  65 —CH₃

—H O S  66 ″ ″

″ ″ O  67 ″

″ ″ ″  68 ″ ″

″ ″  69 ″ ″

—H ″ ″  70 ″ ″

″ ″ ″  71 ″ ″

″ ″ ″  72 ″ ″

″ ″ ″  73 ″ ″

″ ″ ″  74 ″ ″

″ ″ ″  75 ″ ″

″ ″ ″  76 —CH₃

—H O O  77 ″ ″

″ ″ ″  78 ″ ″

″ ″ ″  79 ″ ″

″ ″ ″  80 ″ ″

″ ″ ″  81 ″ ″

″ ″ ″  82 ″ ″

″ ″ ″  83 ″ ″

″ ″ ″  84 ″ ″

″ ″ ″  85 ″ ″

″ ″ ″  86 ″ ″

″ ″ ″  87 —CH₃

—H O O  88 ″ ″

″ ″ ″  89 ″ ″

″ ″ ″  90 ″ ″

″ ″ ″  91 ″ ″

″ ″ ″  92 ″ ″

″ ″ ″  93 ″ ″

″ ″ ″  94 ″ ″

″ ″ ″  95 ″

″ ″ ″  96 ″ ″

″ ″ ″  97 ″ ″

″ ″ ″  98 —CH₃

—H O O  99 ″ ″

″ ″ ″ 100 ″ ″

″ ″ ″ 101 ″ ″

″ ″ ″ 102 ″ ″

″ ″ ″ 103 ″ ″

″ ″ ″ 104 ″ ″

″ ″ ″ 105 ″ ″

″ ″ ″ 106 ″ ″

″ ″ ″ 107 ″ ″

″ ″ ″ 108 ″ ″

″ ″ ″ 109 —CH₃

—H O O 110 ″ ″

″ ″ ″ 111 ″ ″

″ ″ ″ 112 ″ ″

″ ″ ″ 113 ″ ″

″ ″ ″ 114 ″ ″

″ ″ ″ 115 ″ ″

″ ″ ″ 116 ″ ″

″ ″ ″ 117 ″ ″

″ ″ ″ 118 ″ ″

″ ″ ″ 119 ″ ″

″ ″ ″ 120 —CH₃

—H O O 121 ″ ″

″ ″ ″ 122 ″ ″

″ ″ ″ 123 ″

″ ″ S 124 ″ ″

″ ″ ″ 125 ″ ″

″ ″ ″ 126 ″ ″

″ ″ ″ 127 ″ ″

″ ″ ″ 128 ″ ″

″ ″ ″ 129 ″ ″

″ ″ ″ 130 ″ ″

″ ″ ″ 131 —CH₃

—H O S 132 ″ ″

″ ″ ″ 133 ″ ″

″ ″ ″ 134 ″ ″

″ ″ ″ 135 ″ ″

″ ″ ″ 136 ″ ″

″ ″ ″ 137 ″ ″

″ ″ ″ 138 ″ ″

″ ″ ″ 139 ″ ″

″ ″ ″ 140 ″ ″

″ ″ ″ 141 ″ ″

″ ″ ″ 142 —CH₃

—H O S 143 ″ ″

″ ″ ″ 144 ″ ″

″ ″ ″ 145 ″ ″

″ ″ ″ 146 ″ ″

″ ″ ″ 147 ″ ″

″ ″ ″ 148 ″ ″

″ ″ ″ 149 ″ ″

″ ″ ″ 150 ″

″ ″ ″ 151 ″ ″

″ ″ ″ 152 ″ ″

″ ″ ″ 153 —CH₃

—H O S 154 ″ ″

″ ″ ″ 155 ″ ″

″ ″ ″ 156 ″ ″

″ ″ ″ 157 ″ ″

″ ″ ″ 158 ″ ″

″ ″ ″ 159 ″ ″

″ ″ ″ 160 ″ ″

″ ″ ″ 161 ″ ″

″ ″ ″ 162 ″ ″

″ ″ ″ 163 ″

″ ″ O 164 —CH₃

—H O O 165 ″ ″

″ ″ ″ 166 ″ ″

″ ″ ″ 167 ″ ″

″ ″ ″ 168 ″ ″

″ ″ ″ 169 ″ ″

″ ″ ″ 170 ″ ″

″ ″ ″ 171 ″ ″

″ ″ ″ 172 ″ ″

″ ″ ″ 173 ″ ″

″ ″ ″ 174 ″ ″

″ ″ ″ 175 —CH₃

—H O O 176 ″ ″

″ ″ ″ 177 ″ ″

″ ″ ″ 178 ″ ″

″ ″ ″ 179 ″ ″

″ ″ ″ 180 ″ ″

″ ″ ″ 181 ″ ″

″ ″ ″ 182 ″ ″

″ ″ ″ 183 ″

″ ″ ″ 184 ″ ″

″ ″ ″ 185 ″ ″

″ ″ ″ 186 —CH3

—H O O 187 ″ ″

″ ″ ″ 188 ″ ″

″ ″ ″ 189 ″ ″

″ ″ ″ 190 ″ ″

″ ″ ″ 191 ″ ″

″ ″ ″ 192 ″ ″

″ ″ ″ 193 ″ ″

″ ″ ″ 194 ″ ″

″ ″ ″ 195 ″ ″

″ ″ ″ 196 ″ ″

″ ″ ″ 197 —CH₃

—H O O 198 ″ ″

″ ″ ″ 199 ″ ″

″ ″ ″ 200 ″ ″

″ ″ ″ 201 ″ ″

″ ″ ″ 202 ″

″ ″ ″ 203 ″ ″

″ ″ ″ 204 ″ ″

″ ″ ″ 205 ″ ″

″ ″ ″ 206 ″ ″

″ ″ ″ 207 ″ ″

″ ″ ″ 208 —CH₃

—H O O 209 ″ ″

″ ″ ″ 210 ″ ″

″ ″ ″ 211 ″ ″

″ ″ ″ 212 ″ ″

″ ″ ″ 213 ″ ″

″ ″ ″ 214 ″ ″

″ ″ ″ 215 ″ ″

″ ″ ″ 216 ″ ″

″ ″ ″ 217 ″ ″

″ ″ ″ 218 ″ ″

″ ″ ″ 219 —CH₃

—H O O 220 ″ ″

″ ″ ″ 221 ″ ″

″ ″ ″ 222 ″ ″

″ ″ ″ 223 ″

—CH₃ ″ S 224 ″ ″

″ ″ 225 ″ ″

—CH₃ ″ ″ 226 ″ ″

″ ″ ″ 227 ″ ″

″ ″ ″ 228 ″ ″

″ ″ ″ 229 ″

″ ″ ″ 230 —CH₃

O S 231 ″ ″

″ ″ ″ 232 ″ ″

″ ″ ″ 233 ″ ″

″ ″ ″ 234 ″ ″

—CH₃ ″ ″ 235 ″ ″

″ ″ 236 —C₂H₅

—H ″ O 237 ″ ″

″ ″ ″ 238 ″ ″

″ ″ ″ 239 ″ ″

″ ″ ″ 240 ″ ″

″ ″ ″ 241 —C₂H₅

—H O O 242 ″ ″

″ ″ ″ 243 ″ ″

″ ″ ″ 244 ″ ″

″ ″ ″ 245 ″ ″

″ ″ ″ 246 ″ ″

″ ″ ″ 247 ″ ″

″ ″ ″ 123˜ 125 248 ″ ″

″ ″ ″ 249 ″ ″

″ ″ ″ 250 ″ ″

″ ″ ″ 251 ″ ″

″ ″ ″ 252 —C₂H₅

—H O O 107˜ 108 253 ″ ″

″ ″ ″ 254 ″ ″

″ ″ ″ 255 ″ ″

″ ″ ″ 256 ″ ″

—CH₃ ″ ″ 257 ″ ″

″ ″ 258 ″ ″

—CH₃ ″ ″ 259 ″ ″

″ ″ ″ 260 ″

H ″ S 261 ″ ″

″ ″ O 262 ″ ″

—CH₃ ″ S 263 —C₂H₅

—H O S 264 ″ ″

″ ″ ″ 265 ″ ″

—CH₃ ″ ″ 266 —CH═CHBr

H ″ ″ 267 ″ ″

″ ″ O 268 ″ ″

″ ″ ″ 269 ″ ″

″ ″ ″ 270 ″ ″

″ ″ ″ 143˜ 148 271 ″ ″

″ ″ S 272 ″ ″

″ ″ ″ 273 ″ ″

″ ″ ″ 274 —CH═CHBr

—H O S 275 ″ ″

—CH₃ ″ ″ 276 ″

H ″ O 277 ″ ″

″ ″ ″ 278 —CH₃

″ ″ S 279 ″ ″

″ ″ O 280 ″ ″ ″

″ S 281 ″ ″

H ″ ″ 282 ″

″ ″ O 283 ″ ″

″ ″ ″ 284 ″ ″

″ ″ ″ 285 —CH₃

—CH₃ O O 286 ″

H ″ ″ 287 ″ ″

″ ″ ″ 288 ″

″ ″ S 289 ″ ″

″ ″ ″ 290 ″ ″

—CH₃ ″ ″ 291 ″

H ″ ″ 292 ″ ″

″ ″ ″ 293 ″ ″

″ ″ ″ 294 ″

″ ″ O 295 ″ ″

″ ″ ″ 296 —CH₃

—H O O 297 ″ ″

″ ″ ″ 298 ″ ″

″ ″ S 299 ″ ″

″ ″ ″ 300 ″

″ ″ ″ 301 ″ ″

″ ″ ″ 302 ″ ″

″ ″ ″ 303 ″ ″

″ ″ ″ 304 ″

″ ″ O 305 ″ ″

″ ″ ″ 306 ″ ″

″ ″ ″ 307 —CH₃

—H O O 308 ″ ″

″ ″ ″ 309 ″ ″

″ ″ ″ 310 ″ ″

″ ″ S 311 ″ ″

″ ″ ″ 312 ″

″ ″ ″ 313 ″ ″

″ ″ ″ 314 ″ ″

″ ″ ″ 315 ″ ″

″ ″ ″ 316 ″ ″

″ ″ ″ 317 ″ ″

″ ″ ″ 318 —CH₃

—H O S 319 ″ ″

″ ″ ″ 320 ″

″ ″ ″ 321 ″ ″

″ ″ ″ 322 ″ ″

″ ″ ″ 323 ″ ″

″ ″ ″ 324 ″ ″

″ ″ ″ 325 ″ ″

″ ″ ″ 326 ″ ″

″ ″ ″ 327 ″ ″

″ ″ ″ 328 ″

″ ″ O 329 —CH₃

—H O S 330 ″ ″

″ ″ ″ 331 ″ ″

″ ″ ″ 332 ″ ″

″ ″ ″ 333 ″ ″

″ ″ ″ 334 ″ ″

″ ″ ″ 335 ″ ″

″ ″ ″ 336 ″ ″

″ ″ ″ 337 ″ ″

″ ″ ″ 338 ″ ″

″ ″ ″ 339 ″ ″

″ ″ ″ 340 —CH₃

—H O S 341 ″

″ ″ ″ 342 ″

″ ″ ″ 343 ″ ″

″ ″ ″ 344 ″ ″

″ ″ ″ 345 ″ ″

″ ″ ″ 346 —C₂H₅

″ ″ ″ 347 ″ ″

″ ″ ″ 348 ″ ″

″ ″ ″ 349 ″ ″

″ ″ ″ 350 ″ ″

″ ″ ″ 351 —CH═CHBr

—H O S 352 ″ ″

″ ″ ″ 353 ″ ″

″ ″ ″ 354 ″ ″

″ ″ ″ 355 ″ ″

″ ″ ″ 356 ″ ″

″ ″ ″ 357 —C₂H₅

″ ″ O 165˜ 166 358 ″

″ ″ ″ S 106˜ 109 359 ″

″ ″ ″ ″ 155˜ 156 360 ″

″ ″ O 110˜ 112 361 ″

″ ″ ″ ″ 156˜ 158 362 —CH₃

—H O O 157˜ 161 363 —C₂H₅ ″ ″ ″ ″ S 151˜ 153 364 ″

″ ″ ″ ″ 158˜ 160 365 ″

″ ″ O 159˜ 162 366 ″ ″ ″ ″ ″ S 112˜ 116 367 ″ ″

″ ″ O 368 ″ ″ ″ ″ ″ S 369 ″

″ ″ O 370 ″

″ ″ ″ ″ 371 ″

″ ″ ″ ″ 372 —C₂H₅

—H O S 157˜ 160 373 ″

″ ″ ″ ″ 374 ″

″ ″ ″ ″ 375 ″

″ ″ O 376 ″ ″ ″ ″ ″ S 377 ″ ″

″ ″ O 378 ″ ″ ″ ″ ″ S 379 —CH₃

″ ″ ″ 380 ″

″ ″ ″ O 381 ″ ″ ″ ″ ″ S 382 —CH₃

—H O O 383 ″ ″ ″ ″ ″ S 384 ″

″ ″ ″ O 385 ″ ″ ″ ″ ″ S 386 ″

″ ″ ″ O 387 ″ ″ ″ ″ ″ S 388 ″

″ ″ ″ O 389 ″ ″ ″ ″ ″ S 390 ″

″ ″ ″ O 391 ″ ″ ″ ″ ″ S 392 ″

″ ″ ″ 393 ″

″ ″ ″ 394 ″

″ ″ ″ ″ 395 ″

″ ″ ″ O 396 ″ ″ ″ ″ ″ S 397 ″

″ ″ ″ 398 ″ ″ ″ ″ ″ O 399 ″

″ ″ S 400 ″ ″

″ ″ ″ 401 ″

″ ″ O 402 ″ ″ ″ ″ ″ S 403 ″ ″

″ ″ O 404 —CH₃

—H O S 405 ″

″ ″ ″ 406 ″

″ ″ ″ ″ 407 ″

″ ″ ″ ″ 408 ″

″ ″ ″ O 409 ″ ″ ″ ″ ″ S 410 ″

″ ″ O 411 ″

″ ″ ″ S 412 ″

″ ″ ″ ″ 413 ″

″ ″ ″ O 414 ″ ″ ″ ″ ″ S 415 —CH₃

—H O S 416 ″

″ ″ ″ ″ 417 ″

″ ″ ″ ″ 418 ″

″ ″ ″ O 419 ″ ″ ″ ″ ″ S 420 ″

″ ″ O 421 ″ ″ ″ ″ ″ S 422 —C₂H₅ ″ ″ ″ ″ O 423 ″ ″ ″ ″ ″ S 424 —CH₃

″ ″ ″ O 425 ″ ″ ″ ″ ″ S 426 —C₂H₅

—H O O 427 ″ ″ ″ ″ ″ S 428 —CH₃

″ ″ ″ O 429 ″ ″ ″ ″ ″ S 430 —C₂H₅ ″ ″ ″ ″ O 431 ″

″ ″ ″ S 432 —CH₃

″ ″ ″ O 433 ″ ″ ″ ″ ″ S 434 —C₂H₅ ″ ″ ″ ″ O 435 ″ ″ ″ ″ ″ S 436 —CH₃

″ ″ ″ O 437 —CH₃

—H O S 438 —C₂H₅ ″ ″ ″ ″ O 439 ″ ″ ″ ″ ″ S 440 —CH₃

″ ″ ″ O 441 ″ ″ ″ ″ ″ S 442 —C₂H₅

″ ″ ″ O 443 ″ ″ ″ ″ ″ S 444 —CH3

″ ″ ″ O 445 ″ ″ ″ ″ ″ S 445 —C₂H₅ ″ ″ ″ ″ O 447 ″ ″ ″ ″ ″ S 448 —C₂H₅

—H O S 449 ″

″ ″ ″ O 450 ″ ″ ″ ″ ″ S 451 ″

″ ″ ″ O 452 ″ ″ ″ ″ ″ S 453 ″

″ ″ ″ O 454 ″ ″ ″ ″ ″ S 455 ″

″ ″ ″ O 456 ″ ″ ″ ″ ″ S 457 ″

″ ″ ″ O 458 ″ ″ ″ ″ ″ S 459 —C₂H₅

—H ″ S 460 ″

″ ″ ″ O 461 ″ ″ ″ ″ ″ S 462 ″

″ ″ ″ O 463 ″ ″ ″ ″ ″ S 464 ″

″ ″ ″ O 465 ″ ″ ″ ″ ″ S 466 ″

″ ″ ″ O 467 ″ ″ ″ ″ ″ S 468 ″

″ ″ ″ O 469 ″ ″ ″ ″ ″ S 470 —C₂H₅

—H O O 471 ″ ″ ″ ″ ″ S 472 ″

″ ″ ″ O 92.5˜95 473 ″ ″ ″ ″ ″ S 474 ″

″ ″ ″ O 160˜ 160.7 475 ″ ″ ″ ″ ″ S 476 ″

″ ″ O 477 ″ ″ ″ ″ ″ S 478 ″

″ ″ ″ O 479 ″ ″ ″ ″ ″ S 480 ″

″ ″ ″ O 481 —C₂H₅

—H O S 482 ″

″ ″ ″ 483 ″

″ ″ ″ O 484 ″ ″ ″ ″ ″ S 485 —CH₃

″ ″ O 118˜ 120 486 ″

″ ″ O 487 ″ ″ ″ ″ ″ S 488 —C₂H₅ ″ ″ ″ ″ O 489 ″ ″ ″ ″ ″ S 490 —CH₃

″ ″ ″ O 491 ″ ″ ″ ″ ″ S 492 —C₂H₅

—H O O 493 ″ ″ ″ ″ ″ S 494

″ ″ O 495 ″ ″

″ ″ ″ 496 ″ ″

″ ″ ″ 112˜ 114 497 ″ ″ ″ ″ ″ S 138˜ 140 498 ″

″ ″ ″ O 499 ″ ″ ″ ″ ″ S 500 ″

″ ″ ″ O 501

″

″ ″ S 502 ″

″ ″ ″ O 503

−H O S 504 ″

″ ″ ″ O 505 ″ ″ ″ ″ ″ S 506 ″

″ ″ ″ O 507 ″ ″ ″ ″ ″ S 508 ″

″ ″ ″ O 509 ″ ″ ″ ″ ″ S 510 ″

″ ″ ″ O 511 ″ ″ ″ ″ ″ S 512 ″

″ ″ O 138˜ 141 513 ″ ″ ″ ″ ″ S 165˜ 168 514

—H O O 515 ″ ″ ″ ″ ″ S 516 ″

″ ″ ″ O 517 ″ ″ ″ ″ ″ S 518 ″

″ ″ ″ O 519 ″ ″ ″ ″ ″ S 520 ″

″ ″ ″ O 521 ″ ″ ″ ″ ″ S 522 ″

″ ″ ″ O 523 ″ ″ ″ ″ ″ S 524 ″

″ ″ ″ O 525

—H O S 526 ″

″ ″ O 527 ″ ″ ″ ″ ″ S 528 ″

″ ″ ″ O 529 ″ ″ ″ ″ ″ S 530 ″

″ ″ ″ O 531 ″ ″ ″ ″ ″ S 532 ″

″ ″ ″ O 533 ″ ″ ″ ″ ″ S 534 ″

″ ″ ″ O 535 ″ ″ ″ ″ ″ S 536

—H O O 537 ″ ″ ″ ″ ″ S 538 ″

″ ″ ″ O 539 ″ ″ ″ ″ ″ S 540 ″

″ ″ ″ O 541 ″ ″ ″ ″ ″ S 542 ″

″ ″ O 543 ″ ″ ″ ″ ″ S 544 ″

″ ″ ″ O 545 ″ ″ ″ ″ ″ S 546 ″

″ ″ ″ O 547

—H O S 548 ″

″ ″ ″ O 549 ″ ″ ″ ″ ″ S 550 ″

″ ″ ″ O 551 ″ ″ ″ ″ ″ S 552 ″

″ ″ ″ O 553 ″ ″ ″ ″ ″ S 554 ″

″ ″ ″ O 555 ″ ″ ″ ″ ″ S 556 ″

″ ″ O 557 ″ ″ ″ ″ ″ S 558

—H O O 559 ″ ″ ″ ″ ″ S 560 ″

″ ″ ″ O 561 ″ ″ ″ ″ ″ S 562 ″

″ ″ ″ O 563 ″ ″ ″ ″ ″ S 564 ″

″ ″ ″ O 565 ″ ″ ″ ″ ″ S 566 ″

″ ″ ″ O 567 ″ ″ ″ ″ ″ S 568 ″

″ ″ ″ O 569

—H O S 570

″ ″ O 571 ″

″ ″ S 572 ″ ″

″ ″ O 573 ″ ″ ″ ″ ″ S 574 ″

″ ″ O 94˜97 575 ″ ″ ″ ″ ″ S 123˜ 124 576 ″

″ ″ ″ O 577 ″ ″ ″ ″ ″ S 578 ″

″ ″ ″ O 579 ″ ″ ″ ″ ″ S 580

—H O O 581 ″ ″ ″ ″ ″ S 582 ″

″ ″ ″ O 583 ″ ″ ″ ″ ″ S 584 ″

″ ″ ″ O 585 ″ ″ ″ ″ ″ S 586 ″

″ ″ ″ O 587 ″ ″ ″ ″ ″ S 588 ″

″ ″ ″ O 589 ″ ″ ″ ″ ″ S 590 ″

″ ″ O 591

—H O S 592 ″

″ ″ ″ O 593 ″ ″ ″ ″ ″ S 594 ″

″ ″ ″ O 595 ″ ″ ″ ″ ″ S 596 ″

″ ″ ″ O 597 ″ ″ ″ ″ ″ S 598 ″

″ ″ ″ O 599 ″ ″ ″ ″ ″ S 600 ″

″ ″ ″ O 601 ″ ″ ″ ″ ″ S 602

—H O O 603 ″ ″ ″ ″ ″ S 604 ″

″ ″ O 605 ″ ″ ″ ″ ″ S 606 ″

″ ″ ″ O 607 ″ ″ ″ ″ ″ S 608 ″

″ ″ ″ O 609 ″ ″ ″ ″ ″ S 610 ″

″ ″ ″ O 611 ″ ″ ″ ″ ″ S 612 ″

″ ″ ″ O 613

—H O S 614 ″

″ ″ ″ O 615 ″ ″ ″ ″ ″ S 616 ″

″ ″ ″ O 617 ″ ″ ″ ″ ″ S 618 ″

″ ″ O 619 ″ ″ ″ ″ ″ S 620 ″

″ ″ ″ O 621 ″ ″ ″ ″ ″ S 622 ″

″ ″ ″ O 623 ″ ″ ″ ″ ″ S 624

—H O O 625 ″ ″ ″ ″ ″ S 626 ″

″ ″ ″ O 627 ″ ″ ″ ″ ″ S 628 ″

″ ″ ″ O 629 ″ ″ ″ ″ ″ S 630 ″

″ ″ ″ O 631 ″ ″ ″ ″ ″ S 632 ″

″ ″ O 633 ″ ″ ″ ″ ″ S 634 ″

″ ″ ″ O 635

—H O S 636 ″

″ ″ ″ O 637 ″ ″ ″ ″ ″ S 638 ″

″ ″ ″ O 639 ″ ″ ″ ″ ″ S 640 ″

″ ″ ″ O 641 ″ ″ ″ ″ ″ S 642 ″

″ ″ ″ O 643 ″ ″ ″ ″ ″ S 644 ″

″ ″ ″ O 645 ″ ″ ″ ″ ″ S 646 n-C₃H₇

—H O O 647 ″

″ ″ S 648 ″

″ ″ O 649 ″ ″ ″ ″ ″ S 650 ″

″ ″ ″ O 651 ″ ″ ″ ″ ″ S 652 ″

″ ″ ″ O 653 ″ ″ ″ ″ ″ S 654 ″

″ ″ ″ O 655 ″ ″ ″ ″ ″ S 656 ″

″ ″ O 657 n-C₃H₇

—H O S 658 ″

″ ″ ″ O 659 ″ ″ ″ ″ ″ S 660 ″

″ ″ ″ O 661 ″ ″ ″ ″ ″ S 662 ″

″ ″ ″ O 663 ″ ″ ″ ″ ″ S 664 —CH₃

″ ″ S 665 ″

″ ″ ″ O 666 ″ ″ ″ ″ ″ S 667 —CH₂CH₃

″ ″ ″ O 668 —CH₂CH₃

—H O S 669

″ ″ ″ O 670 ″ ″ ″ ″ ″ S 671

″ ″ ″ O 672 ″ ″ ″ ″ ″ S 673 ″

″ ″ ″ O 674 ″ ″ ″ ″ ″ S 675 —C₂H₅

″ ″ O 119˜ 121 676 ″ ″ ″ ″ ″ S 141˜ 142 677 ″

″ ″ ″ O 678 ″ ″ ″ ″ ″ S 679 —C₂H₅

—H O O 680 ″ ″ ″ ″ ″ S 681

″ ″ ″ O 682 ″ ″ ″ ″ ″ S 683 ″

″ ″ ″ O 684 ″ ″ ″ ″ ″ S 685 —C₂H₅

″ ″ O 167˜ 171 686 ″ ″ ″ ″ ″ S 139˜ 141 687

″ ″ ″ O 688 ″ ″ ″ ″ ″ S 689 —C₂H₅

″ ″ O 115˜ 116 690 —C₂H₅

—H O S 134˜ 135 691 ″

″ ″ ″ O 692 ″ ″ ″ ″ ″ S 693 ″

″ ″ ″ O 694 ″ ″ ″ ″ ″ S 695 ″

″ ″ ″ O 696 ″ ″ ″ ″ ″ S 697

″ ″ ″ O 698 ″ ″ ″ ″ ″ S 699 —C₂H₅

″ ″ O 700 ″ ″ ″ ″ ″ S 701 —C₂H₅

—H O O 702 ″ ″ ″ ″ ″ S 703 ″

″ ″ O 704 ″ ″ ″ ″ ″ S 132˜ 134 705 ″

″ ″ ″ O 706 ″ ″ ″ ″ ″ S 707 ″

″ ″ ″ O 708 ″

″ ″ O 709 ″ ″ ″ ″ ″ S 710 ″

″ ″ ″ O 711 ″ ″ ″ ″ ″ S 712 —C₂H₅

—H O O 713 ″ ″ ″ ″ ″ S 714 ″

″ ″ ″ O 715 ″ ″ ″ ″ ″ S 716 ″

″ ″ O 717 ″ ″ ″ ″ ″ S 718 ″

″ ″ ″ O 719 ″ ″ ″ ″ ″ S 720 ″

″ ″ ″ O 721 ″ ″ ″ ″ ″ S 722 ″

″ ″ ″ O 723 —C₂H₅

—H O S 724

″ ″ O 725 ″ ″ ″ ″ ″ S 726 ″

″ ″ ″ O 727 ″ ″ ″ ″ ″ S 728 ″

″ ″ ″ O 729 ″ ″ ″ ″ ″ S 730

″ ″ ″ O 731 ″ ″ ″ ″ ″ S 732 ″

″ ″ O 733 ″ ″ ″ ″ ″ S 734

—H O O 735 ″ ″ ″ ″ ″ S 736 ″

″ ″ ″ O 737 ″ ″ ″ ″ ″ S 738 ″

″ ″ ″ O 739 ″ ″ ″ ″ ″ S 740 ″

″ ″ O 741 ″ ″ ″ ″ ″ S 742 ″

″ ″ ″ O 743 ″ ″ ″ ″ ″ S 744 ″

″ ″ ″ O 745

—H O S 746 ″

″ ″ ″ O 747 ″ ″ ″ ″ ″ S 748 —C₂H₅

″ ″ O 108˜ 110 749 ″ ″ ″ ″ ″ S 136˜ 138 750 ″ ″

″ ″ S 751 ″

″ ″ ″ O 752 ″

″ ″ ″ O 753 ″

″ ″ ″ S 754

″ ″ ″ O 755 ″

″ ″ ″ S 756

—H O O 757 ″

″ ″ ″ S

Compound No. R¹ R² R³ Y Melting point (° C.) 758 —CH₃

O 759 — — — S 760 —C₂H₅ — — O 761 — — — S 762 —CH₃

— O 763 — — — S 764 —C₂H₅ — — O 764 — — — S 766 —CH₃

— O 767 —CH₃

S 768 —C₂H₅ — — O 769 — — — S 770

— O 771 — — — S 772 —

— O 773 — — — S 774 —

— O 775 — — — S 776 —

— O 777 — — — S 778

O 779 — — — S 780 —C₂H₅

O 781 — — — S 782 —

— O 783 — — — S 784 —

— O 785 — — — S 786 —

— O 787 — — — S 788

— O 789

S 790 —

— O 791 — — — S 792 —

— O 793 — — — S 794 —

— O 795 — — — S 796

— O 797 — — — S

The compounds according to the invention of the formula I wherein R³represents methyl or branched alkyl or —CH2—Z(CH₂)_(n)—R⁵ group where R⁵represents a hydrogen, halogen atom, azido, alkoxy, aralkyloxy,optionally substituted aryl group or the like may be prepared inaccordance with the following reaction formula (1), (2) or (3):

wherein R¹, R², R³, R⁴, X and Y have the same meanings definedhereinbefore, X¹ and X² represent a halogen atom, arylthio, alkoxy groupor the like, and M represents an alkaline metal.

Firstly, the compound of the formula II or IV is treated with an organicalkali metal compound in an ether solvent such as diethyl ether andtetrahydrofuran at a temperature of −80° to −10° C. for 0.2 to 10 hours.

Examples of the organic alkali metal compound include potassiumbistrimethylsilylamide, sodium bistrimethylsilylamide and lithiumalkylamide, and particularly preferred compounds among those are lithiumdiisopropylamide (LDA) and lithium 2,2,6,6-tetramethylpiperidide (LTMP).Such lithium alkylamides are preferably prepared immediately before thereaction. For example, lithium dialkylamide may be prepared by reactinga secondary amine such as diisopropylamine with an alkyl lithium such asn-butyl lithium in a solvent such as diethyl ether, dioxane,tetrahydrofuran and dimethoxyethane with stirring under the atmosphereof an inert gas such as argon at −80° C. to −10° C. for 0.2 to 5 hours.

The organic alkali metal compound is usually used in an amount of 1 to 5moles per mole of the compound of the general formula II or IV.

Then, the electrophilic reagent of the general formula R²X¹ or R¹X² isadded to the reaction mixture in a ratio of about 1 to 5 moles to thecompound of the general formula II or IV to allow the reaction under thesame condition as in the reaction with the organic alkali metalcompound.

The electrophilic reagent should have a group of R¹ or R² defined above,and examples of this reagent includes various diaryl disulfides,arylsulfenyl chlorides, dialkyl disulfides, dicycloalkyl disulfides,alkyl halides, aralkyl halides such as benzyl bromide, acid halides suchas benzoyl halide and isobutyric halide, acid anhydrides and estersthereof, aryl-carbonylalkyl halides such as phenacyl chloride and thelike.

The compounds of the general formula II can be prepared by aconventional method.

The compounds of the general formula IV can be prepared in accordancewith the reaction formula (I) above (R¹═H).

wherein R¹, R², R³, R⁴, X and Y have the same meanings definedhereinbefore and X³ represents a halogen atom such as chlorine, bromineand iodine or sulfonyloxy group such as toluenesulfonyloxy and mesyloxygroups.

The compounds of the general formula VI are treated with an acid such ashydrochloric acid and bromic acid in a suitable solvent, for example, analcohol such as methanol and ethanol and water at an appropriatetemperature of from room temperature to 100° C. to obtain the compoundsof the general formula VII.

Then, the compounds of the general formula VII are reacted with thecompounds of the general formula VIII in a suitable solvent such asdimethylformamide, dimethyl sulfoxide, acetonitrile and tetrahydrofuranin the presence of a suitable base such as sodium hydride, sodiumalkoxide, potassium alkoxide, potassium carbonate and sodium carbonateat a temperature of from ambient temperature to the boiling point of thesolvent to obtain the compounds of the general formula I.

The starting compounds represented by the general formula VI can beprepared in accordance with the reaction formula (1) or (2).

When the objective compound has a hydroxyl group of R⁵ or when anyintermediate compound of the reactions has a hydroxyl group, thereactions of (1) and (2) should be carried out using a starting compoundor intermediate compound of which hydroxyl group is protected by anappropriate protective group instead of the unprotected compound of theformula II or IV or the like, and the protective group is theneliminated to obtain the target compound.

Any protective groups conventionally used for the protection of hydroxylgroup may be used for this purpose so long as it is not eliminated underthe alkaline condition.

Examples of such protective group are aralkyl groups such as benzyl,trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, silylgroups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl andt-butyldiphenylsilyl, tetrahydropyranyl group and substituted alkylgroups such as methoxymethyl group. Among those protective groups, silylgroups are particularly preferred.

The introduction of the protective group can be carried out by aconventional method.

For example, the introduction of the protective silyl group may becarried out by reacting the compound having the hydroxyl group with 1 to10 times by mole of silylating reagent such as trimethylsilyl chlorideand t-butyldimethylsilyl chloride at a temperature of from 0° to 50° C.in the presence of a base such as pyridine, picoline, diethylaniline,dimethylaniline, triethylamine and imidazole in a solvent such asdimethylformamide, acetonitrile, tetrahydrofuran and a mixture of thosesolvents in any combination.

The elimination of the protective group may be carried out by aconventional method corresponding to the kind of the protective group,for example, acid hydrolysis, ammonium fluoride treatment or catalyticreduction.

The compounds obtained by the reactions (1), (2) or (3) which have anitro substituted phenylthio group at the 6-position may be convertedinto the compounds having an amino group by hydrogenation in accordancewith the reaction formula (4) below. The hydrogenation can be carriedout in an organic solvent such as alcohol and acetic acid in thepresence of a catalyst such as palladium/carbon at an appropriatetemperature of from room temperature to 80° C.:

wherein the symbols have the same meanings as defined above.

The compounds having an arylthio, alkylthio or cycloalkylthio group canbe converted to corresponding compounds having an arylsulfinyl,alkylsulfinyl or cycloalkylsulfinyl group by using an oxidizing agentsuch as hydrogen peroxide and m-chloroperbenzoic acid in accordance withthe reaction formula (5) below:

wherein R⁶ represents an aryl, alkyl or cycloalkyl group and the othersymbols have the same meanings as defined above.

The compounds having phenyl sulfoxide group can be converted intocorresponding compounds having a substituted arylthio or aryloxy groupby reacting with sodium arylthiolate or sodium aryloxide having varioussubstituents on the benzene ring in an organic solvent such astetrahydrofuran, alcohol, dimethylformamide and acetonitrile at anappropriate temperature of from room temperature to 100° C. inaccordance with the reaction formula (6) below:

wherein A represents a sulfur or oxygen atom, R⁷ and R⁸ independentlyrepresent a halogen atom such as chlorine, bromine, fluorine and iodine,alkyl group such as methyl, ethyl, propyl and butyl, halogenated alkylgroup such as trichloromethyl, alkoxy group such as methoxy, ethoxy,propoxy and butoxy, hydroxyl group, nitro group, amino group, cyanogroup and acyl group such as acetyl, and the other symbols have the samemeanings as defined above.

The present compounds may be also prepared in accordance with, forexample, the reaction formula (7) or (8) below:

wherein R⁹ represents an alkyl group such as methyl and ethyl, arylgroup such as phenyl and toluyl, a protective group such as silyl groupor the like, and the other symbols have the same meanings as definedabove.

The reactions of the formulae (7) and (8) can be carried out in an aminesolvent such as diethylamine and triethylamine in the presence of apalladium catalyst at an appropriate temperature of from roomtemperature to 70° C. The reactions may be carried but morehomogeneously by adding another solvent such as acetonitrile. As thecatalyst, a palladium catalyst of bis(triphenylphosphine)palladiumdichloride, tetrakis(triphenylphosphine)palladium(O) andbis(diphenylphosphino)ethanepalladium dichloride can be used incombination with cuprous iodide.

The present compounds can be prepared also in accordance with thereaction formula (9) or (10) below, and the reactions may be carried outin the same manner as the reactions of the formulae (7) and (8) exceptthat an olefin derivative of H₂C═CH—R₁₀ wherein R₁₀ represents analkoxycarbonyl, nitrile, carbamoyl group and the like is used instead ofthe acetylene derivative in the reactions of the formulae (7) and (8):

wherein the symbols have the same meanings as defined above.

The palladium catalyst may be the same as in the reaction of theformulae (7) and (8).

The compounds according to the invention can be prepared also inaccordance with the reaction formula (11) below:

wherein X⁴ represents a halogen atom such as chlorine, bromine andiodine, and the other symbols have the same meaning as defined above.

The compounds according to the invention can be prepared also inaccordance with the reaction formula (12) or (13) below:

wherein the symbols have the same meanings as defined hereinbefore.

In the reactions of the formulae (12) and (13), intermediate compoundsare prepared in accordance with the reaction formulae (1) and (2) asdescribed hereinbefore except that a compound of OCH-CH(R¹¹)(R¹²)wherein R¹¹ and R¹² independently represent a hydrogen atom, alkyl groupsuch as methyl, ethyl and propyl or aryl group such as phenyl is usedinstead of the compounds R¹X² and R²X¹, and then the intermediatecompounds are dehydrated by a dehydrating agent such as mesyl chloride,tosyl chloride and thionyl chloride to produce the compounds accordingto the invention having an alkenyl group.

By hydrogenation, the alkynyl group of the compounds produced in thereactions of the formula (7) or (8) can be converted into thecorresponding alkenyl or alkyl group and the alkenyl group of thecompound produced in any one of the reactions formulae (9) to (13) canbe converted into the corresponding alkyl group. For the reduction ofalkynyl group into alkenyl group, the hydrogenation may be carried outat an appropriate temperature of from room temperature to 80° C. underhydrogen atmosphere in the presence of a catalyst such aspalladium/barium sulfate, palladium/calcium carbonate, palladium/calciumcarbonate/lead acetate and palladium/barium sulfate/quinoline in asolvent such as alcohol and acetic acid. For the reduction of alkenyl oralkynyl group into alkyl group, the hydrogenation may be carried out byusing a catalyst such as palladium/carbon and palladium hydroxide underthe same conditions as used for producing the alkenyl group.

The 6-benzyl substituted derivatives of the invention may be prepared inaccordance with the reaction formula (14) below:

wherein the symbols have the same meanings as defined hereinbefore

In the reactions of the formula (14), intermediate compounds areprepared in the same way as the reactions of the formula (1) usingOHC-R¹³ where R¹³ represents an optionally substituted aryl group suchas phenyl instead of R¹X² and the intermediate compounds are reduced bya suitable reducing agent to convert the hydroxyl group into a hydrogenatom. The reduction can be carried out by using hydrogen gas in thepresence of palladium/carbon or palladium hydroxide.

The 6-substituted acyclouridine or acyclothymidine derivatives obtainedin the above-described reactions can be converted into 4-thioderivatives by heating them with2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide in asolvent such as toluene and xylene in accordance with the reactionformula (15) below:

wherein the symbols have the same meanings as defined hereinbefore.

The 4-thio derivatives can be also prepared by preparing corresponding4-chloro derivatives by chlorination of corresponding uridine orthymidine derivatives by a chlorinating agent such as phosphorouspentachloride or phosphorous oxychloride and reacting the 4-chloroderivatives with sodium bisulfide.

Further, 4-amino derivatives can be prepared by reacting theacyclouridine or thymidine derivatives with1-(2-mesitylenesulfonyl)-3-nitro-1,2,4-triazole in the presence ofdiphenylphosphoric acid in a solvent such as pyridine to producecorresponding 4-(3-vitro-1,2,4-triazole) derivatives which are convertedto the corresponding 4-amino derivatives by aqueous ammonia at anappropriate temperature of from room temperature to 100° C. inaccordance with the reaction formula (16) below:

wherein the symbols have the same meanings as define hereinbefore.

Thus, the compounds of the invention represented by the formula I′ areprepared as described above.

The above-obtained compounds where R⁴ is a hydrogen atom may beconverted into corresponding compounds having R⁴ other than the hydrogenatom in accordance with the reaction formula (17) below:

wherein X5 represents a halogen atom such as chlorine, bromine andiodine or sulfonyloxy group such as toluenesulfonyloxy and mesyloxy, andthe other symbols have the same meanings as defined hereinbefore.

The reaction of the formula (17) may be carried out in a suitablesolvent such as tetrahydrofuran, acetonitrile, dimethylformamide,pyridine and alcohol in the presence of a base in an amount of 1 to 2times of the starting compound at a suitable temperature from roomtemperature to the boiling point of the solvent. Examples of the baseinclude sodium alkoxide, potassium alkoxide, potassium carbonate, sodiumcarbonate, sodium hydride and the like.

The compounds of the invention where R⁵ is a hydroxy group, which areobtained in any of the reactions of formula (1) to (17), may beconverted into corresponding compounds having a substituted hydroxylgroup in accordance with any of the reaction formulae (18) to (21)below:

wherein R14 represents an optionally branched alkyl group, optionallysubstituted aryl grow or heterocyclic group, X⁶ represents a halogenatom such as chlorine, bromine and iodine or —OCOR¹⁴, and the othersymbols have the same meanings as defined hereinbefore.

The reaction of the formula (18) may be carried out in a suitablesolvent such as tetrahydrofuran, acetonitrile, dimethylformamide,pyridine, dichloromethane and chloroform in the presence of a base in anamount of 1 to 2 times of the starting compound at a suitabletemperature from room temperature to the boiling point of the solvent.Examples of the base include triethylamine, pyridine, imidazole, sodiumcarbonate, potassium carbonate, sodium hydroxide and the like.

wherein R¹⁵ represents an optionally branched alkyl group or aralkylgroup, X⁷ represents a halogen atom such as chlorine, bromine and iodineor —OCOOR¹⁵, and the other symbols have the same meanings as definedhereinbefore.

The reaction of the formula (19) may be carried out in a suitablesolvent such as tetrahydrofuran, acetonitrile, dimethylformamide,pyridine, dichloromethane and chloroform in the presence of a base in asamount of 1 to 2 times of the starting compound at a suitabletemperature from room temperature to the boiling paint of the solvent.Examples of the base include triethylamine, pyridine, imidazole, sodiumcarbonate, potassium carbonate, sodium hydroxide and the

wherein R¹⁶ represents an optionally branched alkyl group or aralkylgroup, X⁸ represents a halogen atom such as chlorine, bromine and iodineor sulfonyloxy group such as toluenesulfonyloxy and mesyloxy, and theother symbols have the same meanings as defined hereinbefore.

The reaction of the formula (20) may be carried out in a suitablesolvent such as tetrahydrofuran, acetonitrile, dimethylformamide,pyridine, dichloromethane and chloroform in the presence of a base in anamount of 1 to 2 times of the starting compound at a suitabletemperature from room temperature to the boiling point of the solvent.Examples of the base include triethylamine, pyridine, imidazole, sodiumcarbonate, potassium carbonate, sodium hydroxide and the like.

wherein R¹⁷ represents an optionally branched alkyl group or aryl group,X⁹ represents an oxygen or sulfur atom, and the other symbols have thesame meanings as defined hereinbefore.

The reaction of formula (21) may be carried out in an appropriatesolvent such as tetrahydrofuran, acetonitrile, dimethylformamide,pyridine, dichloromethane and chloroform at an appropriate temperatureof from room temperature to the boiling point of the solvent.

The compounds of the present invention obtained as describedhereinbefore and represented by the formula I or I′ may be separated andpurified by any of the conventional methods for the separation andpurification of nucleosides, for example, recrystallization, adsorptionchromatography, ion exchange chromatography and the like.

The compound of the invention represented by the formula I or I′ may beconverted into a pharmaceutically acceptable salt thereof by aconventional method. Such salt may be, for example, an alkali metal saltsuch as sodium or potassium salt, alkaline earth salt such as magnesiumsalt, ammonium salt or alkylammonium salt such as methylammonium,dimethylammonium, trimethylammonium, tetramethylammonium salt or thelike.

The compounds according to invention can be administered to human beingsvia any route, oral, rectal, parenteral or local for the prevention ortreatment of the infection of viruses such as retrovirus. Theadministration dose of the compounds according to the invention may bedetermined according to age, physical condition, body weight and thelike of a patient to be treated; however, a suitable daily does of thecompounds is 1 to 100 mg/(body weight)kg, preferably 5 to 50 mg/(bodyweight)kg and it is administered in one to several times.

The compound of the invents is generally prepared in a pharmaceuticalcomposition with a suitable carrier, excipient and other additives.Either a liquid carrier or solid carrier may be suitably used for thepresent antiviral agent.

Examples of the solid carrier are lactose, kaolin, sucrose, crystallinecellulose, corn starch, talc, agar, pectin, stearic acid, magnesiumstearate, lecithin, sodium chloride and the like.

Examples of the liquid are glycerin, peanut oil, polyvinyl pyrrolidone,olive oil, ethanol, benzyl alcohol, propylene glycol, water and thelike.

The present antiviral agent may be made in various forms. For example,it may be in the form of a tablet, powder, granule, capsule;suppository, troche or the like when a solid carrier is used, and it maybe also in the form of syrup, emulsion, soft gelatin capsule, cream,gel, paste, spray, injection solution, or the like when a liquid carrieris used.

The novel 6-substituted ayclopyrimidine nucleoside derivatives accordingto the sent invention have an effective antiviral activity againstviruses such as retrovirus and have a relatively low toxicity againstthe host cell, hence the derivatives of the invention are extremelyuseful as an active ingredient of antiviral agent.

EXAMPLE

The present invention will be further illustrated hereinafter by way ofexamples, but these examples do not limit the invention and manyvariations and modifications can be made without departing from thescope of the present invention.

The numbers of the compounds used in the description of the examplescorrespond to those used in Table 1.

The starting compounds used in the examples such as

1-[(2-hydroxyethoxy)methyl]-6-phenylthio-2-thiothymine,

1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine,

1-[(2-hydroxyethoxy)methyl]-6-(m,m′-dimethylphenylthio)-2-thymine,

1-[(2-hydroxyethoxy)methyl]-6-(m,m′-dimethylphenylthio)-2-thiothymine,

1-[(2-hydroxyethoxy)methyl]-6-(m,m′-dichlorophenylthio)-thymine,

1-[(2-hydroxyethoxy)methyl]-6-benzylthymine,

1-[(2-hydroxyethoxy)methyl]-6-cyclohexylthiothymine,

1-[(2-hydroxyethoxy)methyl]-6-m-tolylthiothymine and the like wereproduced according to the methods described in the examples of PCTInternational Application WO89/09213.

EXAMPLE 1

Preparation of 1-[(2-acetoxyethoxy)methyl]-6-phenylthio-2-thiothymine(compound No. 1)

To 2 ml of pyridine, 0.31 g (1.0 mmole) of1-[(2-hydroxyethoxy)methyl]-6-phenylthio-2-thiothymine and 0.10 ml (1.1mmol of acetic anhydride were added under a flow of nitrogen, allowed toreact for 2 hours at room temperature, concentrated to dryness underreduced pressure and crystallized from ethanol/water to obtain 0.62 g ofthe target compound (Yield: 88%).

EXAMPLES 2-6

Using the following compounds in place of1-[(2-hydroxyethoxy)methyl]-6-phenylthio-2-thiothymine in Example 1,Compounds Nos.2 to 6 in Table 1 were obtained in the same manner asExample 1:

1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine,

1-[(2-hydroxyethoxy)methyl]-6-(m,m′-dimethylphenylthio)thymine,

1-[(2-hydroxyethoxy)methyl]-6-(m,m′-dimethylphenylthio)-2-thiothymine,

1-[(2-hydroxyethoxy)methyl]-6-(m,m′-dichlorophenylthio)thymine, and

1-[(2-hydroxyethoxy)methyl]-6-benzylthymine.

EXAMPLES 7-13

Compounds Nos.7 to 13 in Table 1 were prepared in the same manner asExample 2 by using ethyl formats, i-butyryl chloride, pivaloyl chloride,decanoyl chloride, cyclohexanecarbonyl chloride, benzoyl chloride ornicotinyl chloride respectively in place of acetic anhydride in Example2.

EXAMPLE 14

Compound No. 14 was prepared in the same manner as Example 2 by usingt-butoxycarbonyl chloride in place of acetic anhydride in Example 2.

EXAMPLE 15

Compound No. 15 was obtained in the same manner as Example 2 by using1-[(2-hydroxyethoxy) methyl]-6-cyclohexylthiothymine andbenzyloxycarbonyl chloride in place of1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine and acetic anhydride inExample 2 respectively.

EXAMPLE 16

Preparation of 1-[(2-phenylcarbamoyloxyethoxy)methyl]-6-m-tolylthiothymine (Compound No. 16)

To 2 ml of pyridine, 0.32 g (1.0 mmole) of1-[(2-hydroxyethoxy)methyl]-6-m-tolylthiothymine and 0.12 ml (1.1 mmole)of phenyl isocyanate were added under a flow of nitrogen allowed toreact for 18 hours at room temperature. The reaction mixture wasconcentrated to dryness under reduced pressure and crystallized fromacetone/water to obtain 0.24 g of the target compound (Yield: 54%).

EXAMPLE 17 and 18

Compounds Nos.17 and 18 were prepared in the same manner as Example 16by using ethyl isocyanate or phenyl thioisocyanate respectively in placeof phenyl isocyanate.

EXAMPLE 19

Preparation of 1-[(2-benzyloxyethoxy)methyl]-6-phenylthiothymine(Compound No. 19)

To 4 ml of tetrahydrofuran, 0.17 g (4.2 mmol) of sodium hydride wasadded under a nitrogen flow, and stirred to form a suspension. To thissuspension, a solution of 0.62 g (2.0 mmole) of1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine in 2 ml oftetrahydrofuran was added slowly to react for 45 minutes at roomtemperature. The resultant was added with 0.24 ml (2.0 mmol) of benzylbromide and 7.4 g (20 μmol) of tetrabutylammonium iodide and allowed toreact for 15 hours. The reaction mixture was neutralized with aceticacid and distributed between chloroform and saturated aqueous solutionof sodium by hydrogencarbonate, and the chloroform layer wasconcentrated to dryness under reduced pressure. The residue wasdissolved in a small amount of chloroform, adsorbed on a silica gelcolumn and eluted with 1% methanol/chloroform. The eluate wasconcentrated and crystallized from diethyl ether/hexane to obtain 0.64 gof the target compound (Yield: 80%).

EXAMPLES 20-21

Compounds Nos.20 and 21 were prepared in the same manner as Example 19by using methyl bromide or bromopentane respectively in place of benzylbromide.

EXAMPLE 22

Preparation of 1-(methoxymethyl)-6-phenylthiothymine (Compound No. 22)

To 250 ml of methylene chloride, 25 g (0.20 mol) of thymine and 109 ml(0.44 mol) of bistrimethylsilylacetamide were added under a nitrogenflow, and stirred for 2.5 hours at room temperature. To this mixture, 24g (0.30 mole) of chloromethyl methyl ether and 0.59 g (1.6 mmol) oftetrabutylammonium iodide were added and heated under reflux for 1.5hours. Then, the reaction mixture was added with 400 ml of methanol and100 ml of water slowly and concentrated under reduced pressure. Theresidue was crystallized from ethyl acetate to obtain1-(methoxymethyl)-thymine. Then, 119 ml of lithium diisopropylamide(0.25 mol) solution in tetrahydrofuran (2.1M) was added to 335 ml oftetrahydrofuran under a nitrogen flow at −70° C., to which a suspensionof 17.0 g (0.10 mol) 1-(methoxymethyl)thymine in 107 ml oftetrahydrofuran added dropwise over 30 minutes. After stirring for 2.5hours at −70° C., the reaction mixture was with a solution of 43.6 g ofdiphenyl disulfide in 49 ml of tetrahydrofuran dropwise over 20 minutesand allowed to react for 20 minutes. The reaction mixture was added with35 ml of acetic acid, brought to room temperature and then added with 1l of ethyl acetate. The mixture was washed with water (100 ml×5) andsaturated solution of sodium hydrogencarbonate (twice), dried onmagnesium sulfate and concentrated under reduced pressure. The residuewas crystallized from ethanol to obtain 20 g of the target compound(Yield: 73%).

EXAMPLES 23-26

Compounds Nos.23 to 26 were prepared in the same manner as Example 22 byusing 1-(ethoxymethyl)thymine, 1-[(2-azidoethoxy) methyl]thymine,1-[(2-fluoroethoxy)methyl]thymine or 1-[(2-chloroethoxy)methyl]thyminerespectively in place of 1-(methoxymethyl)thymine.

EXAMPLE 27

Preparation of 6-phenylthiothymine (Compound No. 27)

To 100 ml of concentrated hydrochloric acid, 17.2 g (62 mmole) of1-(methoxymethyl)-6-phenylthiothymine was added and allowed to react for2 hours at 80° C. The reaction mixture was concentrated under reducedpressure and crystallized from ethanol to obtain 3.8 g of the targetcompound (Yield: 26%).

EXAMPLE 28

Preparation of 1-methyl-6-phenylthiothymine (Compound No. 28)

To 1 ml of dimethyl sulfoxide, 20 mg (85 μmol) of 6-phenylthiothymine,2.5 μl (40 μmol) of methyl iodide and 12 mg (85 μmol) of potassiumcarbonate were added and allowed to react for 6 hours at 80° C. Thereaction mixture was concentrated under reduced pressure and adsorbed ona silica gel column and eluted with 1% methanol/chloroform. The eluatewas concentrated and crystallized from diisopropyl ether to obtain 5.0mg of the target compound (Yield: 51%).

EXAMPLES 29-30

Compounds Nos.29 and 30 were prepared in the same manner as Example 28by using ethyl tosylate or n-butyl iodide respectively in place ofmethyl iodide.

EXAMPLE 31

Preparation of 1-(4-hydroxybutyl) -6-phenylthiothymine (Compound No. 31)

To 2 ml of dimethyl sulfoxide, 468 mg (2.0 mmol) of 6-phenythiothymine,358 mg (1.0 mmol) of 4-(t-butyldimethylsiloxy)-butyl-p-toluenesulphonateand 276 mg (2.0 mmol) of potassium carbonate were added and heated toreact for 4 hours at 80° C. The reaction mixture was concentrated underreduced pressure, added with methanol and filtered. The filtrate wasconcentrated under reduced pressure, added with 20 ml of tetrahydrofuranand 1 ml of 1N hydrochloric acid and stirred for 90 minutes. Thereaction mixture was concentrated under reduced pressure and adsorbed ona silica gel column and eluted with 2% methanol/chloroform The eluatewas concentrated and crystallized from acetone/hexane to obtain 12.0 mgof the target compound (Yield: 4%).

EXAMPLE 32

Preparation of 1-(methylthiomethyl)-6-phenylthiothymine (Compound No.32)

To 4 ml of dimethylformamide, 0.17 ml (2.0 mmol) ofchloromethylmethylsulfide, 0.47 g (2.0 mmol) of 6-phenylthiothymine,0.56 ml (2.0 mmol) of triethylamine were added and allowed to react for22 hours at room temperature. The reaction mixture was concentratedunder reduced pressure and the residue was adsorbed on a silica gelcolumn and eluted with chloroform. The eluate was concentrated andcrystallized from ethyl acetate to obtain 45 mg of the target compound(Yield: 8%).

EXAMPLE 33

Preparation of 1-[(2-hydroxyethoxy)methyl]-3-benzyl-6-phenylthiothymine(Compound No. 33)

To 2 ml of dimethylformamide 0.62 g (2.0 mmol) of1-[(2-hydroxyethoxy)methyl]-6-penylthiothymine, 0.26 ml (2.2 mmol) ofbenzyl bromide and 0.38 ml (2.2 mmol) of ethyldiisopropylamine wereadded and allowed to react for 5 days at room temperature under nitrogenatmosphere. The reaction mixture was concentrated under reduced pressureand the residue was adsorbed on a silica gel column and eluted with 1%methano/chloroform to obtain 0.24 g of the target compound (Yield: 30%).

EXAMPLE 34

Compounds No. 34 was prepared in the same manner as Example 33 by usingmethyl iodide in place of benzyl bromide.

EXAMPLE 35

Preparation of 1-ethoxymethyl-5-ethyl-6-phenylthiouracil (Compound No.247)

To 100 ml of methylene chloride 5.1 g (40 mmol) of 5-ethyluracil and 22ml (0.88 mmol) of bistrimethylsilylacetamide were added under a nitrogenatmosphere and stirred for 40 minutes at room temperature. To thismixture, 4.1 ml (88 mmole) of chloromethyl yl ether and 0.15 g (0.4mmol) of tetrabutylammonium iodide were added and heated under refluxfor 15 hours. Then, the reaction mixture was poured carefully into 50 mlof saturated aqueous solution of sodium hydrogencarbonate and filteredthrough Celite. The organic layer was washed with water, dried onmagnesium sulfate and concentrated under reduced pressure. The residuewas crystallized from ethyl acetate to obtain 6.4 g of (ethoxymethyl)5-ethyluracil (Yield: 81%).

Then, 2.2 ml of lithium diisopropylamide (4.4 mmol) solution intetrahydrofuran (2.1M) was added to 6 ml of tetrahydrofuran under anitrogen atmosphere at −70° C., to which a solution of 0.40 g (2.0 mmol)of 1-ethoxymethyl-5-ethyluracil in 3 ml of tetrahydrofuran was addeddropwise over 15 minute. After stirring for 1 hour at −70° C., thereaction mixture was added with a solution of 0.57 g of diphenyldisulfide in 2 ml of tetrahydrofuran dropwise over 10 minutes andallowed to react for 30 minutes. The reaction mixture was added with 1ml of acetic acid, brought to room temperature and then added with 30 mlof ethyl acetate. The mixture was washed with water (3 mix 5) andsaturated aqueous solution of sodium hydrogencarbonate (twice), dried onmagnesium sulfate and′ concentrated under reduced pressure. The residuewas purified by silica gel chromatography (ethyl acetate/hexane=3:17)and crystallized from ethyl acetate to obtain 0.61 g of1-ethoxymethyl-5-ethyl-6-phenylthiouracil (Yield: 32%).

EXAMPLE 36

Compound No. 357 was obtained in the same way as Example 35 by using3,3′,5,5′-tetramethylphenyl disulfide in place of diphenyl disulfide.

EXAMPLE 37

Preparation of 1-ethoxymethyl-5-ethyl-6-phenylthio-2-thiouracil(Compound No. 358)

To 100 ml of methylene chloride, 5.1 g (40 mmol) of 2-thiouracil and 22ml (88 mmol) of bistrimethylsilylacetamide were added under a nitrogenatmosphere, and stirred for 40 minutes at room temperature. To thismixture, 8.2 ml

(88 mmole) of chloromethyl ethyl ether and 0.15 g (0.4 mmol) oftetrabutylammonium iodide were added and heated under reflux for 15hours. Then, the reaction mixture was poured carefully into 50 ml ofsaturated aqueous solution of sodium hydrogencarbonate and filteredthrough Celite. The organic layer was washed with water, dried onmagnesium sulfate and concentrated under reduced pressure. The residuewas crystallized from ethyl acetate to obtain 1.1 g of1-ethoxymethyl-2-thiouracil (Yield: 15%).

Then, 3.3 ml lithium diisopropylamide solution in tetrahydrofuran (2.1M)was added to 9 ml of tetrahydrofuran under a nitrogen atmosphere at −70°C., to which a solution of 0.56 g (3.0 mmol) of1-ethoxymethyl-2-thiouracil in 3 ml of tetrahydrofuran was addeddropwise over 15 minutes. After stirring for 1 hour at −70° C., thereaction mixture was added with a solution of 0.85 g (3.9 mmol) ofdiphenyl disulfide in 1 ml of tetrahydrofuran dropwise over 10 minutesand allowed to react for 20 minutes. The reaction mixture was added with1 ml of acetic acid, brought to room temperature and then added with 30ml of ethyl acetate. The mixture was washed with water (3 ml×5) andsaturated aqueous solution of sodium hydrogencarbonate (twice), dried onmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (ethyl acetate/hexane=3:17),crystallized from ethyl acetate to obtain 0.64 g of1-ethoxymethyl-6-phenylthio-2-thiouracil (Yield: 73%).

Then, 2.1 ml of 1.6M butyl lithium (3.4 mmol) solution in hexane wasadded to a solution of 0.57 ml (3.4 mmol) 2,2,6,6-tetramethylpyperidinein 8 ml of tetrahydrofuran under a nitrogen atmosphere at −70° C.,warmed to −50° C., and stirred for 20 minutes. After cooling to −70° C.again, the mixture was added with a solution of 0.44 g (1.5 mmol) of1-ethoxymethy-6-phenylthio-2-thiouracil in 4 ml tetrahydrofuran dropwiseover 15 minutes, stirred for an hour, added with 1.2 ml (15 mmol) ethyliodide and stirred for 19 hours. Then, the mixture was added with 1 mlacetic acid, brought to room temperature, added with 30 ml ethylacetate, washed with water and saturated aqueous solution of sodiumchloride, dried on magnesium sulfate and concentrated under reusedpressure. The residue was purified by silica gel chromatography (ethylacetate/hexane=3:17) and crystallized from ethyl acetate to obtain 96 mgof the title compound (Yield: 20%).

EXAMPLE 38

Compound No. 359 was prepared in the same way as Example 37 by using3,3′,5,5′-tetramethyldiphenyl disulfide in place of diphenyl disulfide.

EXAMPLE 39

Compound No. 360 was prepared in the same way as Example 35 by usingbenzyl chloromethyl ether in place of chloromethyl ethyl ether.

EXAMPLE 40

Compound No. 361 was prepared in the same way as Example 35 by usingbenzyl chloromethyl ether and 3,3′,5,5′-tetramethyldiphenyl disulfiderespectively in place of chloromethyl ethyl ether and diphenyldisulfide.

EXAMPLE 41

Compound No 362 was prepared in the same way as Example 35 by usingthymine and benzyl chloromethyl ether in place of 5-ethyluracil andchloromethyl ethyl ether.

EXAMPLE 42

Compound No. 41 was prepared in the same way as Example 22 by usingchloromethyl propyl ether in place of chloromethyl methyl ether.

EXAMPLE 43

Compound No. 485 was prepared in the same way as Example 22 by usingbutyl chloromethyl ether in place of chloromethyl methyl ether.

EXAMPLE 44

Compound No. 365 was prepared in the same way as Example 35 by using3,3′,5,5′-tetrachlorodiphenyl disulfide in place of diphenyl disulfide.

EXAMPLE 45

Compound No. 366 was prepared in the same way as Example 35 by using5-ethyl-2-thiouracil and 3,3′,5,5′-tetrachlorodiphenyl disulfiderespectively in place of 5-ethyluracil and diphenyl disulfide.

EXAMPLE 46

Compound No. 496 was prepared in the same way as Example 35 by using5-isopropyluracil in place of 5-ethyluracil.

EXAMPLE 47

Compound No. 497 was prepared in the same way as Example 35 by using5-isopropyl-2-thiouracil in place of 5-ethyluracil.

EXAMPLE 48

Compound No. 574 was prepared in the same way as Example 35 by using5-cyclopropyluracil in place of 5-ethyluracil.

EXAMPLE 49

Compound No. 575 was prepared in the same way as Example 35 by using5-cyclopropyl-2-thiouracil in place of 5-ethyluracil.

EXAMPLE 50

Compound No. 675 was prepared in the same way as Example 35 by usingchloromethyl isopropyl other in place of chloromethyl ethyl ether.

EXAMPLE 51

Compound No. 675 was prepared in the same way as Example 35 by using5-ethyl-2-thiouracil and chloromethyl isopropyl ether respectively inplace of 5-ethyluracil and chloromethyl ethyl ether.

EXAMPLE 52

Compound No. 685 was prepared in the same way as Example 35 by usingchloromethyl cyclohexyl ether in place of chloromethyl ethyl ether.

EXAMPLE 53

Compound No. 686 was prepared in the same way as Example 35 by using5-ethyl-2-thiouracil and chloromethyl cyclohexyl ether respectively inplace of 5-ethyluracil and chloromethyl ethyl ether.

EXAMPLE 54

Compound No. 689 was prepared in the same way as Example 35 by usingchloromethyl cyclohexylmethyl ether in place of chloromethyl ethylether.

EXAMPLE 55

Compound No. 690 was prepared in the same way as Example 35 by using5-ethyl-2-thiouracil and chloromethyl cyclohexylmethyl etherrespectively in place of 5-ethyluracil and chloromethyl ethyl ether.

EXAMPLE 56

Compound No. 512 was prepared in the same way as Example 35 by using5-isopropyluracil and benzyl chloromethyl ether respectively in place of5-ethyluracil and chloromethyl ethyl ether.

EXAMPLE 57

Compound No. 513 was prepared in the same way as Example 35 by using5-isopropyl-2-thiouracil and benzyl chloromethyl ether respectively inplace of 5-ethyluracil and chloromethyl ethyl ether.

EXAMPLE 58

Compound No. 748 was prepared in the same way as Example 35 by usingchloromethyl phenetyl ether in place of chloromethyl ethyl ether.

EXAMPLE 59

Compound No. 749 was prepared in the same way as Example 35 by using5-ethyl-2-thioracil and chloromethyl phenetyl ether respectively inplace of 5-ethyluracil and chloromethyl ethyl ether.

EXAMPLE 60

Compound No. 372 was prepared in the same way as Example 35 by using5-ethyl-2-thiouracil and chloromethyl 4-methylbenzyl ether respectivelyin place of 5-ethyluracil and chloromethyl ethyl ether.

EXAMPLE 61

Compound No. 704 was prepared in the same way as Example 35 by using5-ethyl-2-thiouracil and 4-chlorobenzyl chloromethyl ether respectivelyin place of 5-ethyluracil and chloromethyl ethyl ether.

EXAMPLE 62

Preparation of 6-benzyl-1-ethoxymethyl-5-ethyluracil (Compound No. 472)

To 100 ml of methylene chloride, 5.1 g (40 mmol) of 5-ethyluracil and 22ml (88 mmol) of bistrimethylsilylacetamide were added under a nitrogenatmosphere and stirred for 40 minutes at room temperature. To thismixture, 4.1 ml (88 mmole) of chloromethyl ethyl ether and 0.15 g (0.4mmol) of tetrabutylammonium iodide were added and heated under refluxfor 15 hours. Then, the reaction mixture was poured into 50 ml ofsaturated sodium bicarbonate solution carefully and filtered throughCelite. The organic layer was washed with water, dried on magnesiumsulfate and concentrated under reduced pressure. The residue wascrystallized from ethyl acetate to obtain 6.4 g of1-ethoxymethyl-5-ethyluracil (Yield: 81%).

Then, 2.2 ml (4.4 mmol) of lithium diisopropylamide solution intetrahydrofuran (2.1M) was added to 6 ml of tetrahydrofuran under anitrogen atmosphere at −70° C., to which a solution of 0.40 g (2.0 mmol)of 1-ethoxymethyl-5-ethyluracil in 3 ml of tetrahydrofuran was addeddropwise over 15 minutes. After stirring for 1 hour at −70° C., thereaction mixture was added with a solution of 0.27 g (2.6 mmol) ofbenzaldehyde in 2 ml of tetrahydrofuran dropwise over 10 minutes andallowed to react for 30 minutes. The reaction mixture was added with 1ml of acetic acid, brought to room temperature and then added with 30 mlof ethyl acetate. The mixture was washed with water (3 ml ×5) andsaturated aqueous solution of sodium hydrogencarbonate (twice), dried onmagnesium sulfate and concentrated under reduced pressure.

The residue was dissolved in 10 ml of ethanol, added with 20 mg of 20%palladium hydroxide/carbon and stirred under a hydrogen atmosphere for aday at 55° C. Then, after removing the catalyst by filtration, thereaction mixture was concentrated. The residue was crystallized fromhexane to obtain 0.28 g of 6 -benzyl-1-ethoxymethyl-5-ethyluracil(Yield: 85%).

EXAMPLE 63

Compound No. 474 was prepared in the same way as Example 62 by using3,5-dimethylbenzaldehyde in place of benzaldehyde.

EXAMPLE 64

Preparation of 1-butyl-5-ethyl-6-phenylthiouracil (compound No. 252)

To a solution of 5.6 g (40 mmol) of 5-ethyluracil in 60 ml ofdimethylformamide, 5.5 g (40 mmol) of potassium carbonate and 2.3 ml (20mmol) of n-iodobutane were added and stirred for 2 hours at 120° C. Thereaction mixture was concentrated under reduced pressure and distributedbetween dichloromethane and aqueous solution of ammonium chloride, andthe organic layer was concentrated under reduced pressure. The residuewas adsorbed on a silica gel column and eluted with 30% ethylacetate/hexane to obtain 2.7 g of 1-butyl-5-ethyluracil (Yield: 69%).

Then, a solution of 4.4 mmol of lithium diisopropylamide in 2.8 ml oftetrahydrofuran was added dropwise to a solution of 392 mg (2.0 mmol)1-butyl-5-ethyluracil in 9 ml of tetrahydrofuran under a nitrogenatmosphere at −70° C. and stirred for 70 minutes at −70° C. and further5 minutes at −25° C. The mixture was cooled to −70° C. again, added witha solution of 567 mg (2.6 mmol) diphenyl disulfide in 3 ml oftetrahydrofuran, stirred for 20 minutes, added with 1 ml of acetic acid,brought to room temperature, washed with saturated aqueous solution ofsodium chloride and concentrated under reduced pressure. The residue wasadsorbed on a silica gel, eluted with 10% ethyl acetate/hexane andcrystallized from hexane to obtain 40 mg of1-butyl-5-ethyl-6-phenylthiouracil (Yield: 7%).

EXAMPLE 65

Compound No. 363 was prepared in the same way as Example 35 by using5-ethyl-2-thiouracil and benzyl chloromethyl ether respectively in placeof 5-ethyluracil and chloromethyl ethyl ether.

EXAMPLE 66

Compound No. 364 was prepared in the same way as Example 35 by using5-ethyl-2-thiouracil, benzyl chloromethyl ether and3,3′,5,5′-tetramethyldiphenyl disulfide respectively in place of5-ethyluracil, chloromethyl ethyl ether and diphenyl disulfide.

EXAMPLE 67

Preparation of 5-(2-(E)-bromovinyl)-1-(ethoxymethyl)-6-(phenylthio)uracil (Compound No. 270)

In 50 ml of dichloromethane, 4.76 g (20 mmol) of 5-iodouracil wassuspended and added with 11 ml (45 mmol) of bistrimethylsilylacetamideand stirred for 15 minutes at room temperature to form a homogeneoussolution. This solution was added with 2.04 ml (22 mmol) of chloromethylethyl ether and 60 mg of tetra-n-butylammonium iodide and heated underreflux for 3 hours. After the solvent was evaporated under reducedpressure, the residue was added with water to produce crystals, whichwere taken by filtration. The crystals were washed by suspending them inhot methanol and recovering them by cooling and filtration to obtain5.43 g of 1-(ethoxy-methyl)-5-iodouracil.

Then, 1.184 g (4 mmol) of 1-(ethoxymethyl)-5-iodouracil, 870 μg (8 mmol)of ethyl acrylate, 45 mg of palladium acetate and 0.6 ml oftriethylamine were dissolved in 40 ml of dimethylformamide, heated andstirred for 5 hours at 70° C. After the solvent was evaporated underreduced pressure, the residue was adsorbed on a silica gel column,eluted with a solution of dichloromethan/ethyl acetate (1:1 v/v) torecover the desired fraction, from which the solvent was evaporatedunder reduced pressure to obtain 798 mg of5-(2-(E)-carboethoxyvinyl)-1-(ethoxymethyl)uracil as crystals.

Then, 0.16 g (4.0 mmol) of sodium hydroxide and 0.54 g (2.0 mmol) of5-(2- (E) -carboethoxyvinyl) -1- (ethoxymethyl) -uracil were added to 8ml of water, stirred for 4.5 hours, neutralized with 1N hydrochloricacid and added with 10 ml of dimethylformamide to obtain a homogeneoussolution.

This solution was then added with 0.62 g (4.5 mmol) of potassiumcarbonate, stirred for 5 minutes at room temperature to make it ahomogeneous solution, then added with 0.36 g (2.0 mmol) ofN-bromosuccinimide and stirred for 30 minutes. The reaction mixture wasconcentrated under reduced pressure and distributed between chloroformand aqueous solution of ammonium chloride, and the organic layer wasconcentrated under reduced pressure. The residue was adsorbed on asilica gel column and eluted with 20% ethyl acetate/hexane to collectthe desired fraction, from which the solvent was evaporated underreduced pressure to obtain 0.15 g of5-(2-(E)-bromovinyl)-1-(ethoxymethyl)uracil (Yield: 28%).

Then, a solution of 0.15 g (0.56 mmol) 5-(2-(E)-bromovinyl)-1-ethoxymethyl)uracil in 1.7 ml of tetrahydrofuran was added dropwiseto a solution of 1.22 mmol of lithium diisopropylamide in 2.3 ml oftetrahydrofuran under a nitrogen atmosphere at −70° C. over 7 minutesand stirred for 40 minutes, added with a solution of 0.16 g (0.73 mmol)diphenyl disulfide in 1 ml of tetrahydrofuran and stirred for 1 hour.The reaction mixture was washed with saturated aqueous solution ofsodium chloride and concentrated under reduced pressure. The residue wasabsorbed on a silica gel column, eluted with 15% ethyl acetate/hexane tocollect the desired faction, from which the solvent was evaporated underreduced pressure to obtain 11 mg of the target compound (Yield: 5%.m.p.: 143°-148° C.).

Compounds No. 35 to 40, 42 to 246, 248 to 251, 253 to 269, 271 to 356,367 to 371, 373 to 471, 473, 475 to 484, 486 to 495, 498 to 511, 514 to573, 576 to 674, 677 to 684, 687, 688, 691 to 703, 705 to 747 and 750 to803 in Table 1 may be prepared similarly according to the methodsdescribed in the working examples above.

EXAMPLE 68

Production of tablet

1-[(2-acetoxyethoxy)methyl]-6-phenylthiothymine 10 g Corn starch 65 gCarboxycellulose 20 g Polyvinyl pyrrolidone  3 g Calcium stearate  2 gTotal weight 100 g 

The above-mentioned components were well mixed and tablets were producedby a direct tableting method. Each tablet had a weight of 100 mg andcontained 10 mg of 1-](2-acetoxyethoxy)methyl]-6-phenylthiothymine 1-[(2 -acetoxyethoxy)methyl]- 6 -phenylthiothymine.

EXAMPLE 69

Production of powder and encapsulated medicine

1-[2-acetoxyethoxy)methyl]-6-phenylthiothymine 20 g Crystallinecellulose 80 g Total weight 100 g 

Both powder components were well mixed to obtain a powder formulation.100 mg of the thus-obtained powder was charged into a hard capsule ofNo. 5 to obtain an encapsulated medicine.

EXAMPLE 70

Inhibitory activity for HIV infection

In RPMI 1640 DM culture medium containing 20 mM of Hepes buffersolution, 10% fetal bovine serum and 20 μg/ml of gentamycin, 3×10⁴ MT-4cells (human T cell clone which is destroyed by the infection of HIV)were infected with HIV in an amount of 100 times as large as expected tocause 50% infection of the cells. Immediately thereafter, apredetermined amount of sample was added to the culture medium using 50mg/ml sample solutions in dimethyl sulfoxide and the cells were culturedat 37° C.

After 5 days of incubation, the number of existing cells was counted todetermine the concentration of the compound for preventing the death of50% of the MT-4 cells. Separately, MT-4 cells were cultured in the sameway as above except that they were not infected with HIV to determinethe concentration of the compound at which 50% of the MT-4 cells weredestroyed.

Both results are shown in Table 2.

TABLE 2 50% inhibitory 50% cytotoxic Compound concentration ofconcentration to No. HIV infection (μM) MT-4 cells (μM) 1 2.8 196 2 6.7314 3 <0.8 236 4 <0.8 240 5 1.8 218 7 7.1 292 8 9.9 218 10 11 162 11 7.578 12 7.6 53 13 11 170 14 12 66 16 21 420 17 0.96 171 20 8.6 292 22 2.1244 23 <0.8 215 24 5.7 169 25 1.1 191 26 1.7 193 29 4.3 96 30 1.2 89 3113 249 32 1.2 154 41 5.6 147 247 0.016 123 252 0.016 45 357 0.005 >100358 0.026 81 359 0.004 >100 360 0.0025 30 361 0.005 >20 362 0.076 133363 0.0078 >10 364 0.0069 >20 365 0.0074 45 366 0.013 45 372 0.012 >20472 0.041 245 474 0.0064 >500 485 4.7 83 496 0.012 106 497 0.014 >100512 0.0027 >20 513 0.0068 >20 574 0.10 223 575 0.095 46 675 0.34 143 6760.22 >100 685 3.8 >100 686 1.6 223 689 0.45 17 690 0.35 >100 704 0.01220 748 0.096 38 749 0.091 >20

What is claimed is:
 1. A pyrimidine derivative represented by thefollowing formula (I):

wherein R¹ represents C₁ to C₅ alkyl; C₃ to C₈ cycloalkyl; C₂ to C₅alkenyl optionally substituted by one or more substituents selected fromthe group consisting of a halogen atom, phenyl, cyano, C₂to C₆alkoxycarbonyl and carbamoyl groups; C₂ to C₅ alkynyl optionallysubstituted by one or more substituents selected from the groupconsisting of a halogen atom, phenyl, cyano, C₂ to C₆ alkoxycarbonyl andcarbamoyl groups; C₂ to C₅ alkylcarbonyl optionally substituted by oneor more substituents selected from the group consisting of a halogenatom, phenyl, cyano, C₂ to C₆ alkoxycarbonyl and carbamoyl groups; C₇ toC₁₃ arylcarbonyl optionally substituted by one or more substituentsselected from the group consisting of a halogen atom, phenyl, cyano, C₂to C₆ alkoxycarbonyl and carbamoyl groups; C₈ to C₁₄ arylcarbonylalkyloptionally substituted by one or more substituents selected from thegroup consisting of a halogen atom, phenyl, cyano, C₂ to C₆alkoxycarbonyl and carbamoyl groups; C₆ to C₁₂ arylthio optionallysubstituted by one or more substituents selected from the groupconsisting of a halogen atom, phenyl, cyano, C₂ to C₆ alkoxycarbonyl andcarbamoyl groups; C₇ to C₁₃ arylcarbonyl optionally substituted by oneor more substituents selected from the group consisting of a halogenatom, phenyl, cyano, C₂ to C₆ alkoxycarbonyl and carbamoyl groups; C₈ toC₁₄ arylcarbonylalkyl optionally substituted by one or more substituentsselected from the group consisting of a halogen atom, phenyl, cyano, C₂to C₆ alkoxycarbonyl and carbamoyl groups; C₆ to C₁₂ arylthio optionallysubstituted by one or more substituents selected from the groupconsisting of a halogen atom, phenyl, cyano, C₂ to C₆ alkoxycarbonyl andcarbamoyl groups; or C₇ to C₁₇ aralkyl group optionally substituted byone or more substituents selected from the group consisting of a halogenatom, phenyl, cyano, C₂ to C₆ alkoxycarbonyl and carbamoyl groups, R²represents C₆ to C₁₀ arylthio optionally substituted by one or moresubstituents selected from the group consisting of a halogen atom, C₁ toC₅ alkyl, C₁ to C₅ halogenated alkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl,nitro, amino, cyano, and C₂ to C₇ acyl groups; C₁ to C₅ alkylthiooptionally substituted by one or more substituents selected from thegroup consisting of a halogen atom, C₁ to C₅ alkyl, C₁ to C₅ halogenatedalkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl, nitro, amino, cyano and C₂ toC₇ acyl groups; C₃ to C₁₀ cycloalkylthio optionally substituted by oneor more substituents selected from the group consisting of a halogenatom, C₁ to C₅ alkyl, C₁ to C₅ halogenated alkyl, C₁ to C₅ alkoxy,phenyl, hydroxyl, nitro, amino, cyano and C₂ to C₇ acyl groups; C₆ toC₁₂ arylsulfinyl optionally substituted by one or more substituentsselected from the group consisting of a halogen atom, C₁ to C₅ alkyl, C₁to C₅ halogenated alkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl, nitro,amino, cyano and C₂ to C₇ acyl groups; C₁ to C₅ alkylsulfinyl optionallysubstituted by one or more substituents selected from the groupconsisting of a halogen atom, C₁ to C₅ alkyl, C₁ to C₅ halogenatedalkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl, nitro, amino, cyano and C₂ toC₇ acyl groups; C₃ to C₁₀ cycloalkylsulfinyl optionally substituted byone or more substituents selected from the group consisting of a halogenatom, C₁ to C₅ alkyl, C₁ to C₅ halogenated alkyl, C₁ to C₅ alkoxy,phenyl, hydroxyl, nitro, amino, cyano and C₂ to C₇ acyl groups; C₂ to C₅alkenyl optionally substituted by one or more substituents selected fromthe group consisting of a halogen atom, C₁ to C₅ alkyl, C₁ to C₅halogenated alkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl, nitro, amino,cyano and C₂ to C₇ acyl groups; C₂ to C₅ alkynyl optionally substitutedby one or more substituents selected from the group consisting of ahalogen atom, C₁ to C₅ alkyl, C₁ to C₅ halogenated alkyl, C₁ to C₅alkoxy, phenyl, hydroxyl, nitro, amino, cyano and C₂ to C₇ acyl groups;C₇ to C₁₁ aralkyl optionally substituted by one or more substituentsselected from the group consisting of a halogen atom, C₁ to C₅ alkyl, C₁to C₅ halogenated alkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl, nitro,amino, cyano and C₂ to C₇ acyl groups; C₇ to C₁₃ arylcarbonyl optionallysubstituted by one or more substituents selected from the groupconsisting of a halogen atom, C₁ to C₅ alkyl, C₁ to C₅ halogenatedalkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl, nitro, amino, cyano and C₂ toC₇ acyl groups; C₈ to C₁₄ arylcarbonylalkyl optionally substituted byone or more substituents selected from the group consisting of a halogenatom, C₁ to C₅ alkyl, C₁ to C₅ halogenated alkyl, C₁ to C₅ alkoxy,phenyl, hydroxyl, nitro, amino, cyano and C₂ to C₇ acyl groups; or C₆ toC₁₂ aryloxy group optionally substituted by one or more substituentsselected from the group consisting of a halogen atom, C₁ to C₅ alkyl, C₁to C₅ halogenated alkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl, nitro,amino, cyano and C₂ and C₇ acyl groups; R³ represents ethyl; C₃ to C₁₀branched alkyl; or —CH₂—Z(CH₂)_(n)—R⁵ group where R⁵ represents ahydrogen atom; halogen atom; hydroxyl; nicotinoyloxy; formyloxy; C₂ toC₁₁ alkylcarbonyloxy; C₄ to C₁₁ cycloalkylcarbonyloxy; C₈ to C₁₂aralkylcarbonyloxy; C₇ to C₁₃ arylcarbonyloxy; azido; C₂ to C₁₁alkoxycarbonyloxy optionally substituted by one or more substituentsselected from the group consisting of a halogen atom, C₆ to C₁₂ aryl, C₁to C₅ alkoxy and C₁ to C₅ halogenated alkyl groups; C₂ to C₁₁N-alkylcarbamoyloxy optionally substituted by one or more substituentsselected from the group consisting of a halogen atom, C₆ to C₁₂ aryl, C₁to C₅ alkyl, C₁ to C₅ alkoxy and C₁ to C₅ halogenated alkyl groups; C₇to C₁₃ N-arylcarbamoyloxy optionally substituted by one or moresubstituents selected from the group consisting of a halogen atom, C₆ toC₁₂ aryl, C₁ to C₅ alkyl, C₁ to C₅ alkoxy and C₁ to C₅ halogenated alkylgroups; C₂ to C₁₁ N-alkylthiocarbamoyloxy optionally substituted by oneor more substituents selected from the group consisting of a halogenatom, C₆ to C₁₂ aryl, C₁ to C₅ alkyl, C₁ to C₅ alkoxy and C₁ to C₅halogenated alkyl groups; C₇ to C₁₃ N-arylthiocarbamoyloxy optionallysubstituted by one or more substituents selected from the groupconsisting of a halogen atom, C₆ to C₁₂ aryl, C₁ to C₅ alkyl, C₁ to C₅alkoxy and C₁ to C₅ halogenated alkyl groups; C₁ to C₁₀ alkoxyoptionally substituted by one or more substituents selected from thegroup consisting of a halogen atom, C₆ to C₁₂ aryl, C₁ to C₅ alkyl, C₁to C₅ alkoxy and C₁ to C₅ halogenated alkyl groups; C₇ to C₁₃ aralkyloxyoptionally substituted by one or more substituents selected from thegroup consisting of a halogen atom, C₆ to C₁₂ aryl, C₁ to C₅ alkyl, C₁to C₅ alkoxy and C₁ to C₅ halogenated alkyl groups; C₃ to C₁₀ branchedalkyl optionally substituted by one or more substituents selected fromthe group consisting of a halogen atom, C₆ to C₁₂ aryl, C₁ to C₅ alkyl,C₁ to C₅ alkoxy and C₁ to C₅ halogenated alkyl groups; C₃ to C₁₀cycloalkyl optionally substituted by one or more substituents selectedfrom the group consisting of a halogen atom, C₆ to C₁₂ aryl, C₁ to C₅alkyl, C₁ to C₅ alkoxy and C₁ to C₅ halogenated alkyl groups; or C₆ toC₁₂ aryl group optionally substituted by one or more substituentsselected from the group consisting of a halogen atom, C₆ to C₁₂ aryl, C₁to C₅ alkyl, C₁ to C₅ alkoxy and C₁ to C₅ halogenated alkyl groups, Zrepresents an oxygen atom, sulfur atom or methylene group, and nrepresents 0 or an integer of 1 to 5, R⁴ represents a hydrogen atom; Xand Y independently represent an oxygen or sulfur atom; provided thatwhen R⁴ represents a hydrogen atom and Z represents an oxygen atom ormethylene group, R⁵ does not represent hydroxyl group, or apharmaceutically acceptable salt thereof.
 2. A pyrimidine derivativerepresented by the following formula (I′):

wherein: R¹ represents C₁ to C₅ alkyl; C₃ to C₈ cycloalkyl; C₂ to C₅alkenyl optionally substituted by one or more substituents selected fromthe group consisting of a halogen atom, phenyl, cyano, C₂ to C₆alkoxycarbonyl and carbamoyl groups; C₂ to C₅ alkynyl optionallysubstituted by one or more substituents selected from the groupconsisting of a halogen atom, phenyl, cyano, C₂ to C₆ alkoxycarbonyl andcarbamoyl groups; C₂ to C₅ alkylcarbonyl optionally substituted by oneor more substituents selected from the group consisting of a halogenatom, phenyl, cyano, C₂ to C₆ alkoxycarbonyl and carbamoyl groups; C₇ toC₁₃ arylcarbonyl optionally substituted by one or more substituentsselected from the group consisting of a halogen atom, phenyl, cyano, C₂to C₆ alkoxycarbonyl and carbamoyl groups; C₈ to C₁₄ arylcarbonylalkyloptionally substituted by one or more substituents selected from thegroup consisting of a halogen atom, phenyl, cyano, C₂ to C₆alkoxycarbonyl and carbamoyl groups; C₆ to C₁₂ arylthio optionallysubstituted by one or more substituents selected from the groupconsisting of a halogen atom, phenyl, cyano, C₂ to C₆ alkoxycarbonyl andcarbamoyl groups; or C₇ to C₁₇ aralkyl group optionally substituted byone or more substituents selected from the group consisting of a halogenatom, phenyl, cyano, C₂ to C₆ alkoxycarbonyl and carbamoyl groups, R²represents C₆ to C₁₀ arylthio optionally substituted by one or moresubstituents selected from the group consisting of a halogen atom, C₁ toC₅ alkyl, C₁ to C₅ halogenated alkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl,nitro, amino, cyano, and C₂ to C₇ acyl groups; C₁ to C₅ alkylthiooptionally substituted by one or more substituents selected from thegroup consisting of a halogen atom, C₁ to C₅ alkyl, C₁ to C₅ halogenatedalkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl, nitro, amino, cyano and C₂ toC₇ acyl groups; C₃ to C₁₀ cycloalkylthio optionally substituted by oneor more substituents selected from the group consisting of a halogenatom, C₁ to C₅ alkyl, C₁ to C₅ halogenated alkyl, C₁ to C₅ alkoxy,phenyl, hydroxyl, nitro, amino, cyano and C₂ to C₇ acyl groups; C₆ toC₁₂ arylsulfinyl optionally substituted by one or more substituentsselected from the group consisting of a halogen atom, C₁ to C₅ alkyl, C₁to C₅ halogenated alkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl, nitro,amino, cyano and C₂ to C₇ acyl groups; C₁ to C₅ alkylsulfinyl optionallysubstituted by one or more substituents selected from the groupconsisting of a halogen atom, C₁ to C₅ alkyl, C₁ to C₅ halogenatedalkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl, nitro, amino, cyano and C₂ toC₇ acyl groups; C₃ to C₁₀ cycloalkylsulfinyl optionally substituted byone or more substituents selected from the group consisting of a halogenatom, C₁ to C₅ alkyl, C₁ to C₅ halogenated alkyl, C₁ to C₅ alkoxy,phenyl, hydroxyl, nitro, amino, cyano and C₂ to C₇ acyl groups; C₂ to C₅alkenyl optionally substituted by one or more substituents selected fromthe group consisting of a halogen atom, C₁ to C₅ alkyl, C₁ to C₅halogenated alkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl, nitro, amino,cyano and C₂ to C₇ acyl groups; C₂ to C₅ alkynyl optionally substitutedby one or more substituents selected from the group consisting of ahalogen atom, C₁ to C₅ alkyl, C₁ to C₅ halogenated alkyl, C₁ to C₅alkoxy, phenyl, hydroxyl, nitro, amino, cyano and C₂ to C₇ acyl groups;C₇ to C₁₁ aralkyl optionally substituted by one or more substituentsselected from the group consisting of a halogen atom, C₁ to C₅ alkyl, C₁to C₅ halogenated alkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl, nitro,amino, cyano and C₂ to C₇ acyl groups; C₇ to C₁₃ arylcarbonyl optionallysubstituted by one or more substituents selected from the groupconsisting of a halogen atom, C₁ to C₅ alkyl, C₁ to C₅ halogenatedalkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl, nitro, amino, cyano and C₂ toC₇ acyl groups; C₈ to C₁₄ arylcarbonylalkyl optionally substituted byone or more substituents selected from the group consisting of a halogenatom, C₁ to C₅ alkyl, C₁ to C₅ halogenated alkyl, C₁ to C₅ alkoxy,phenyl, hydroxyl, nitro, amino, cyano and C₂ to C₇ acyl groups; or C₆ toC₁₂ aryloxy group optionally substituted by one or more substituentsselected from the group consisting of a halogen atom, C₁ to C₅ alkyl, C₁to C₅ halogenated alkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl, nitro,amino, cyano and C₂ to C₇ acyl groups; R³ represents ethyl; C₃ to C₁₀branched alkyl; or —CH₂—Z(CH₂)_(n)—R⁵ group where R⁵ represents ahydrogen atom; halogen atom; hydroxyl; nicotinoyloxy; formyloxy; C₂ toC₁₁ alkylcarbonyloxy; C₄ to C₁₁ cycloalkylcarbonyloxy; C₈ to C₁₂aralkylcarbonyloxy; C₇ to C₁₃ arylcarbonyloxy; azido; C₂ to C₁₁alkoxycarbonyloxy optionally substituted by one or more substituentsselected from the group consisting of a halogen atom, C₆ to C₁₂ aryl, C₁to C₅ alkyl, C₁ to C₅ alkoxy and C₁ to C₅ halogenated alkyl groups; C₂to C₁₁ N-alkylcarbamoyloxy optionally substituted by one or moresubstituents selected from the group consisting of a halogen atom, C₆ toC₁₂ aryl, C₁ to C₅ alkyl, C₁ to C₅ alkoxy and C₁ to C₅ halogenated alkylgroups; C₇ to C₁₃ N-arylcarbamoyloxy optionally substituted by one ormore substituents selected from the group consisting of a halogen atom,C₆ to C₁₂ aryl, C₁ to C₅ alkyl, C₁ to C₅ alkoxy and C₁ to C₅ halogenatedalkyl groups; C₂ to C₁₁ N-alkylthiocarbamoyloxy optionally substitutedby one or more substituents selected from the group consisting of ahalogen atom, C₆ to C₁₂ aryl, C₁ to C₅ alkyl, C₁ to C₅ alkoxy and C₁ toC₅ halogenated alkyl groups; C₇ to C₁₃ N-arylthiocarbamoyloxy optionallysubstituted by one or more substituents selected from the groupconsisting of a halogen atom, C₆ to C₁₂ aryl, C₁ to C₅ alkyl, C₁ to C₅alkoxy and C₁ to C₅ halogenated alkyl groups; C₁ to C₁₀ alkoxyoptionally substituted by one or more substituents selected from thegroup consisting of a halogen atom, C₆ to C₁₂ aryl, C₁ to C₅ alkyl, C₁to C₅ alkoxy and C₁ to C₅ halogenated alkyl groups; C₇ to C₁₃ aralkyloxyoptionally substituted by one or more substituents selected from thegroup consisting of a halogen atom, C₆ to C₁₂ aryl, C₁ to C₅ alkyl, C₁to C₅ alkoxy and C₁ to C₅ halogenated alkyl groups; C₃ to C₁₀ branchedalkyl optionally substituted by one or more substituents selected fromthe group consisting of a halogen atom, C₆ to C₁₂ aryl, C₁ to C₅ alkyl,C₁ to C₅ alkoxy and C₁ to C₅ halogenated alkyl groups; C₃ to C₁₀cycloalkyl optionally substituted by one or more substituents selectedfrom the group consisting of a halogen atom, C₆ to C₁₂ aryl, C₁ to C₅alkyl, C₁ to C₅ alkoxy and C₁ to C₅ halogenated alkyl groups; or C₆ toC₁₂ aryl group optionally substituted by one or more substituentsselected from the group consisting of a halogen atom, C₆ to C₁₂ aryl, C₁to C₅ alkyl, C₁ to C₅ alkoxy and C₁ to C₅ halogenated alkyl groups, Zrepresents an oxygen atom, sulfur atom or methylene group, and nrepresents 0 or an integer of 1 to 5, and Y represents an oxygen orsulfur atom, or a pharmaceutically acceptable salt thereof.
 3. Acompounds pyrimidine derivative according to claim 1 or 2, wherein: R¹represents C₁ to C₅ alkyl; C₃ to C₈ cycloalkyl; C₂ to C₅ alkenyloptionally substituted by one or more substituents selected from thegroup consisting of a halogen atom, phenyl, cyano, C₂ to C₆alkoxycarbonyl and carbamoyl groups; C₂ to C₅ alkynyl optionallysubstituted by one or more substituents selected from the groupconsisting of a halogen atom, phenyl, cyano, C₂ to C₆ alkoxycarbonyl andcarbamoyl groups; C₂ to C₅ alkylcarbonyl; C₇ to C₁₃ arylcarbonyl; C₉ toC₁₄ arylcarbonylalkyl; C₆ to C₁₂ arylthio; or C₇ to C₁₇ aralkyl group,R² represents C₆ to C₁₀ arylthio optionally substituted by one or moresubstituents selected from the group consisting of a halogen atom, C₁ toC₅ alkyl, C₁ to C₅ halogenated alkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl,nitro, amino, cyano and C₂ to C₇ acyl groups; C₁ to C₅ alkylthio; C₃ toC₁₀ cycloalkylthio optionally substituted by one or more substituentsselected from the group consisting of a halogen atom, C₁ to C₅ alkyl, C₁to C₅ halogenated alkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl, nitro,amino, cyano and C₂ to C₇ acyl groups; C₆ to C₁₂ arylsulfinyl; C₁ to C₅arylsulfinyl; C₃ to C₁₀ cycloalkylsulfinyl; C₂ to C₅ alkenyl; C₂ to C₅alkynyl; C₇ to C₁₁ aralkyl optionally substituted by one or moresubstituents selected from the group consisting of a halogen atom, C₁ toC₅ alkyl, C₁ to C₅ halogenated alkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl,nitro, amino, cyano and C₂ to C₇ acyl groups; C₇ to C₁₃ arylcarbonyl; C₈to C₁₄ arylcarbonylalkyl; or C₆ to C₁₂ aryloxy, R³ represents ethyl; or—CH₂—Z—(CH₂)_(n)—R⁵ group where R⁵ represents a hydrogen atom; halogenatom; hydroxyl; nicotinoyloxy; formyloxy; C₂ to C₁₁ alkylcarbonyloxy; C₄to C₁₁ cycloalkylcarbonyloxy; C₈ to C₁₂ aralkylcarbonyloxy; C₇ to C₁₃arylcarbonyloxy; azido; C₂ to C₁₁ alkoxycarbonyloxy; C₂ to C₈N-alkylcarbamoyloxy; C₇ to C₁₃ N-arylcarbamoyloxy optionally substitutedby one or more substituents selected from the group consisting of ahalogen atom, C₆ to C₁₂ aryl, C₁ to C₅ alkyl, C₁ to C₅ alkoxy and C₁ toC₅ halogenated alkyl groups; C₂ to C₈ N-alkylthiocarbamoyloxy; C₇ to C₁₃N-arylthiocarbamoyloxy optionally substituted by one or moresubstituents selected from the group consisting of a halogen atom, C₆ toC₁₂ aryl, C₁ to C₅ alkyl, C₁ to C₅ alkoxy and C₁ to C₅ halogenated alkylgroups; C₁ to C₁₀ alkoxy; C₇ to C₁₃ aralkyloxy optionally substituted byone or more substituents selected by the group consisting of a halogenatom, C₆ to C₁₂ aryl, C₁ to C₅ alkyl, C₁ to C₅ alkoxy and C₁ to C₅halogenated alkyl groups; C₃ to C₅ branched alkyl; C₅ to C₇ cycloalkyl;or C₆ to C₁₂ aryl group optionally substituted by one or moresubstituents selected from the group consisting of a halogen atom, C₆ toC₁₂ aryl, C₁ to C₅ alkyl, C₁ to C₅ alkoxy and C₁ to C₅ halogenated alkylgroups, Z represents an oxygen atom, sulfur atom or methylene group, andn represents 0 or an integer of 1 to 5; or a pharmaceutically acceptablesalt thereof.
 4. A compound pyrimidine derivative according to claim 3,wherein: R¹ represents C₁ to C₅ alkyl; C₃ to C₈ cycloalkyl; or C₂ to C₅alkenyl optionally substituted by one or more substituents selected fromthe group consisting of a halogen atom, phenyl, cyano, C₂ to C₆alkoxycarbonyl and carbamoyl groups, R² represents C₆ to C₁₀ arylthiooptionally substituted by one or more substituents selected from thegroup consisting of a halogen atom, C₁ to C₅ alkyl, C₁ to C₅ halogenatedalkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl, nitro, amino, cyano and C₂ toC₇ acyl groups; C₃ to C₁₀ cycloalkylthio optionally substituted by oneor more substituents selected from the group consisting of a halogenatom, C₁ to C₅ alkyl, C₁ to C₅ halogenated alkyl, C₁ to C₅ alkoxy,phenyl, hydroxyl, nitro, amino, cyano and C₂ to C₇ acyl groups; or C₇ toC₁₁ aralkyl optionally substituted by one or more substituents selectedfrom the group consisting of a halogen atom, C₁ to C₅ alkyl, C₁ to C₅halogenated alkyl, C₁ to C₅ alkoxy, phenyl, hydroxyl, nitro, amino,cyano and C₂ to C₇ acyl groups, R³ represents ethyl; or—CH₂—Z—(CH₂)_(n)—R⁵ group where R⁵ represents a hydrogen atom; halogenatom; hydroxyl; nicotinoyloxy; formyloxy; C₂ to C₁₁ alkylcarbonyloxy; C₄to C₁₁ cycloalkylcarbonyloxy; C₈ to C₁₂ aralkylcarbonyloxy; C₇ to C₁₃arylcarbonyloxy; azido; C₂ to C₁₁ alkoxycarbonyloxy; C₂ to C₈N-alkylcarbamoyloxy; C₇ to C₁₃ N-arylcarbamoyloxy; C₂ to C₈N-alkylthiocarbamoyloxy; C₇ to C₁₃ N-arylthiocarbamoyloxy; C₁ to C₁₀alkoxy; C₇ to C₁₃ aralkyloxy; C₃ to C₅ branched alkyl; C₅ to C₇cycloalkyl; or C₆ to C₁₂ aryl group optionally substituted by one ormore substituents selected from the group consisting of a halogen atom,C₆ to C₁₂ aryl, C₁ to C₅ alkyl, C₁ to C₅ alkoxy and C₁ to C₅ halogenatedalkyl groups, Z represents an oxygen, sulfur or methylene group, and nrepresents 0 or an integer of 1 to 5; or a pharmaceutically acceptablesalt thereof.
 5. A compound pyrimidine derivative according to claim 4,wherein: R¹ represents C₁ to C₅ alkyl, R² represents a phenylthio groupoptionally substituted by a C₁ to C₃ alkyl or halogen atom; or a benzylgroup optionally substituted by a C₁ to C₃ alkyl or halogen atom, R³represents a —CH₂—Z—(CH₂)_(n)—R⁵ group where R⁵ represents a hydrogenatom; or a phenyl group optionally substituted by a ₁ to ₃ alkyl or ahalogen atom, Z represents an oxygen atom, and n represents an integerof 1 to 3, R⁴ represents a hydrogen atom, X represents an oxygen atom,and Y represents an oxygen atom or sulfur atom; or a pharmaceuticallyacceptable salt thereof.
 6. A compound pyrimidine derivative accordingto claim 5, wherein: R¹ represents an ethyl or isopropyl group, R²represents a phenylthio group optionally substituted by a C₁ to C₃ alkylor halogen atom; R³ represents a —CH₂—Z—(CH₂)_(n)—R⁵ group where R⁵represents a hydrogen atom; Z represents an oxygen atom, and nrepresents an integer of 1 to 3, R⁴ represents a hydrogen atom, Xrepresents an oxygen atom, and Y represents an oxygen or sulfur atom; ora pharmaceutically acceptable salt thereof.
 7. A compound pyrimidinederivative according to claim 6 5, wherein: R¹ represents an ethyl orisopropyl group, R² represents a benzyl group optionally substituted bya a C₁ to C₃ alkyl or halogen atom, R³ represents a —CH₂—Z—(CH₂)_(n)—R⁵group where R⁵ represents a hydrogen atom; Z represents an oxygen atom,and n represents an integer of 1 to 3, R⁴ represents a hydrogen atom, Xrepresents an oxygen atom, and Y represents an oxygen atom or sulfuratom; or a pharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition containing a 6-substituted acyclopyrimidine nucleosidepyrimidine derivative or a pharmaceutically acceptable salt thereofaccording to any one of claims 1-7 claim 1, in admixture with apharmaceutical vehicle.
 9. A pharmaceutical composition according toclaim 8, which has effective antiviral activity.
 10. A pharmaceuticalcomposition according to claim 8, which has effective antiretroviralactivity.
 11. The pharmaceutical composition of claim 8, which is usedto treat a vital viral infection which is susceptible to treatment. 12.A pyrimidine derivative having the following structure:

or a pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition containing the pyrimidine derivative of claim 12 incombination with a pharmaceutically acceptable carrier.
 14. A method oftreating an HIV infection in a host, comprising administering to thehost an effective treatment amount of the pyrimidine derivative of claim12.
 15. A pharmaceutical composition containing a pyrimidine derivativeor a pharmaceutically acceptable salt thereof according to claim 2, inadmixture with a pharmaceutical vehicle.